PATENT DOCUMENT

Abstract:
The present invention relates to peptides comprising amino acids according to Formula I 
       ((X) l (Y) m ) n   (I)
 
     wherein l, m and n are integers from 0 to 10; X and Y, which may be the same or different, are an amino acid selected from the group consisting of hydrophobic amino acids and/or cationic amino acids, together with methods for the use of the peptides in the treatment of microbial infections.

Full Description:
REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a divisional of U.S. patent application Ser. No. 11/573,770, filed Feb. 15, 2007, which is a continuation of International Patent Application No. PCT/GB2005/003245, filed Aug. 18, 2005, which claims priority to U.S. patent application Ser. No. 11/079,795 filed Mar. 14, 2005, now abandoned, and United Kingdom Patent Application No. 0418414.9, filed Aug. 18, 2004. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention provides antimicrobial peptides. The invention further relates to pharmaceutical compositions comprising the antimicrobial peptides and the use of the peptides in the treatment of, inter alia, microbial infections. 
       BACKGROUND OF THE INVENTION 
       [0003]    One major family of endogenous antibacterial peptides, the beta-defensins, are secreted by the epithelial cells that line the digestive, respiratory and urogenital tracts of higher mammals. They are also produced by keratinocytes within the skin. Their primary role is to provide an essential first line of defense against infection via these routes by pathogenic organisms. 
         [0004]    The defensins are one of the most studied classes of antimicrobial peptides. This class consists of cysteine-rich molecules with three disulphide bridges. They are found in plants, insects and various mammals. In humans, two classes of defensin are found which differ from one another in terms of spacing and bonds between the six cysteine residues. The first of these classes is the alpha-defensins (six types) that have been isolated from neutrophils (HNP1-4, human neutrophil peptide) and in the paneth cells of the gastrointestinal tract (alpha-defensins 5 and 6). The second class, the beta-defensins, are longer, more basic, and are expressed throughout the mucosae within the epithelial cells and keratinocytes that line and/or comprise and/or are present within the digestive, respiratory and urogenital tracts, and the skin. hBD1 (human beta-defensin 1) is secreted constitutively and human beta-defensins 2, 3 and 4 (hBD2, hBD3 and hBD4) are produced in response to infection or inflammation. hBD2 expression and secretion is triggered by bacterial stimulation, particularly flagellated bacteria (Harder et al, Nature 1997; 387:861), and IL1α and IL1β (Liu et al, J. Invest. Dermatol. 2002; 118; 275-281). In some tissue sites, Tumor Necrosis Factor alpha (TNF-alpha) and Lipopolysaccharide (LPS) may also play a role in inducing hBD2 expression. In vitro experiments have revealed that hBD2 is active against Gram negative bacteria such as  Escherichia coli  ( E. coli ) and to a lesser extent, Gram positive bacteria such as  Streptococcus pneumoniae  ( Str. pneumoniae ). hBD2 also demonstrates killing activity in vitro against the yeast  Candida albicans . hBD3 expression and secretion is induced by bacterial stimulation, TNF-alpha and especially Interferon-gamma (IFNγ) which also have the common property of being molecules involved in inflammatory processes. 
         [0005]    In addition to the potent, constitutive and regulated broad-spectrum innate antimicrobial protection that the beta-defensins provide, these molecules, hBD2 in particular, also have the ability to mobilize the adaptive arm of the immune response through chemotactic effects on immature dendritic cells and memory T-lymphocytes (Yang et al, Science 1999; 286: 525-528). 
         [0006]    Importantly, evidence is coming to light that beta-defensins not only provide defense against infection from pathogenic microbes, but are key in regulating and maintaining optimal density and diversity of the body&#39;s essential commensal microbial ecosystems, such as those on the skin, and within the gastrointestinal and genital tracts (Ganz, T, Nat. Rev. Immunol. 2003 3(9): 710-20). 
         [0007]    The mode of action of beta-defensins is such that they are largely non-toxic to host cells at active concentrations. The beta-defensins have, therefore, been implicated as potential targets for therapeutics for a wide range of infections. However, natural forms of defensins are technically challenging to produce in recombinant systems resulting in low yields. Moreover, evidence is growing to suggest that, through their chemotactic actions, beta-defensins are potent inflammatory compounds (Yang et al, Science 1999; 286: 525-528; Van Wetering et al., Inflamm. Res. 2002; 51(1): 8-15; Niyonsaba et al. Curr. Drug Targets Inflamm. Allergy 2003; 2(3): 224-231). Taken together, these factors make natural defensins unsuitable for therapeutic applications. 
         [0008]    Beta-defensins are also highly salt sensitive (Porter et al., Infect. Immun. 1997; 65(6): 2396-401; Bals et al., J. Clin. Invest. 1998; 102(5): 874-80; Valore et al., J. Clin. Invest. 1998; 101(8): 1633-42; Goldmann et al., Cell 1997; 88(4): 553-609; Singh et al., Proc. Natl. Acad. Sci. USA 95(25): 14961-6). For this reason, beta-defensins cannot provide antimicrobial protection in conditions such as cystic fibrosis wherein, although the respiratory epithelia produce abundant beta-defensins in response to the persistent bacterial infections associated with this condition, they are inactive due to the imbalance in ion transport across the respiratory epithelial membranes that results in increased cation resorption (Na+ in particular) and increased chloride secretion (Donaldson S H and Boucher R C. Cum Opin. Pulm. Med. 2003 November; 9(6):486-91; Davies J C. Pediatr. Pulmonol. Suppl. 2004; 26:147-8.) 
         [0009]    There is a requirement, therefore, for further agents that can be used to treat microbial infections. 
       SUMMARY OF THE INVENTION 
       [0010]    The present inventors have identified peptides that, surprisingly, have improved antimicrobial activity over natural defensins. 
         [0011]    According to a first aspect of the invention, there is provided a peptide comprising from 3 to about 200 D and/or L amino acids, which may be the same or different, wherein the amino acids are selected from the group consisting of hydrophobic amino acids and/or cationic amino acids. The peptide may comprise 3 to about 100 D and/or L amino acids, for example 3 to 50 D and/or L amino acids including 4 to about 50 D and/or L-amino acids. The peptides of the invention are useful, inter alia, in the treatment or prevention of microbial infections. 
         [0012]    In a further aspect of the invention there is provided a peptide comprising amino acids according to the formula I: 
         [0000]      ((X) l (Y) m ) n   (I)
 
         [0000]    wherein 1 and m are integers from 0 to 10, for example 0 to 5; n is an integer from 1 to 10; X and Y, which may be the same or different, are an amino acid selected from the group consisting of hydrophobic amino acids and/or cationic amino acids. 
         [0013]    In a preferred aspect of the invention, the peptide comprises from 3 to 200 amino acids, for example 3, 4, 5, 6 or 7 up to 100 amino acids, including 3, 4, 5, 6, or 7 up to 20, 25, 30, 35, 40 or 42 amino acids. 
         [0014]    The peptide according to the invention may comprise 100 to 200 amino acids, 27 to 100 amino acids, 28 to 86 amino acids, 7 to 27 amino acids or 3 to 14 amino acids. 
         [0015]    Preferably the peptides comprise 3 to 15 amino acids, for example 3 to 7 amino acids. 
         [0016]    In a further preferred aspect, the peptides comprise one or more cysteine residues, for example up to 6 cysteine residues, such as 1, 2, 3, 4, 5 or 6 cysteine residues. 
         [0017]    In a preferred aspect of the invention, there is provided a peptide comprising amino acids according to the Formula II: 
         [0000]      C((X) l (Y) m ) n C((X) l (Y) m ) n   (II)
 
         [0000]    wherein C is cysteine, 1, n and m are an integer from 0 to 10; and X and Y, which may be the same or different, are an amino acid selected from the group consisting of hydrophobic amino acids and/or cationic amino acids. 
         [0018]    In a further preferred aspect of the invention, the peptide comprises amino acids according to the Formula III: 
         [0000]      C((X) l (Y) m ) n C((X) l (Y) m ) n C((X) l (Y) m ) n C((X) l (Y) m ) n C  (III)
 
         [0000]    wherein C, X, Y, l, m and n are as defined herein. 
         [0019]    In a yet further preferred aspect of the invention, the peptide comprises amino acids according to the Formula IV 
         [0000]      C((X) l (Y) m ) n C((X) l (Y) m ) n C((X) l (Y) m ) n C((X) l (Y) m ) n CC  (IV)
 
         [0000]    wherein C, X, Y, l, m and n are as defined herein. 
         [0020]    Since the peptides of the invention are simpler in structure than natural beta-defensins, they are simple and efficient to produce. The peptides are also substantially salt insensitive and are not hepatotoxic. Moreover, their mode of action, being physical rather than metabolic (i.e. direct membrane disruption versus targeting components of vital metabolic pathways), minimizes, if not rules out, the probability that target microbes can develop resistance to these antimicrobial agents. 
         [0021]    As known to the skilled person, amino acids can be placed into different classes depending primarily upon the chemical and physical properties of the amino acid side chain. For example, some amino acids are generally considered to be hydrophilic or polar amino acids and others are considered to be hydrophobic or nonpolar amino acids. As used herein, the terms “hydrophobic” and “cationic” may refer to amino acids having a hydrophobicity that is greater than or equal to −1.10 and/or a net charge that is greater than or equal to 0 as described in Fauchere and Pliska, Eur. J. Med. Chem. 10:39 (1983). A hydrophobic or nonpolar amino acid may also refer to an amino acid having a side chain that is uncharged at physiological pH, that is not polar and that is generally repelled by aqueous solution. 
         [0022]    In a preferred aspect of the invention, X and/or Y are selected from the group of hydrophobic amino acids consisting of glycine, leucine phenylalanine, proline, alanine, tryptophan, valine, isoleucine, methionine, tyrosine and threonine, and/or the group of cationic amino acids consisting of ornithine, histidine, arginine and lysine. X and/or Y may be D or L-amino acids. Moreover, X and/or Y may be alternating amino acids. 
         [0023]    The invention also includes known isomers (structural, stereo-, conformational and/or configurational) and structural analogues of the above amino acids, and those modified either naturally (e.g. post-translational modification) or chemically, including, but not exclusively, phosphorylation, glycosylation, sulfonylation and/or hydroxylation. 
         [0024]    In general, the peptides of the invention do not include the amino acids aspartic acid, glutamic acid, asparagine, glutamine or serine, but certain peptides of the invention may have activity even though these amino acids are present. 
         [0025]    The peptides of the invention may include one or more additional amino acid residues adjacent to one or both of the terminal cysteine residues of formula II, III or IV, for example, the peptides may comprise up to 10 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) additional amino acid residues. Preferably, the additional amino acids are non-cysteine residues. More preferably, the additional amino acids are X and/or Y. 
         [0026]    In addition, the amino acid sequence of a peptide can be modified so as to result in a peptide variant that includes the substitution of at least one amino acid residue in the peptide for another amino acid residue, including substitutions that utilize the D rather than L form. 
         [0027]    One or more of the residues of the peptide can be exchanged for another to alter, enhance or preserve the biological activity of the peptide. Such a variant can have, for example, at least about 10% of the biological activity of the corresponding non-variant peptide. Conservative amino acids are often utilized, i.e. substitutions of amino acids with similar chemical and physical properties as described above. 
         [0028]    Hence, for example, conservative amino acid substitutions may involve exchanging lysine for arginine, ornithine or histidine; exchanging one hydrophobic amino acid for another. After the substitutions are introduced, the variants are screened for biological activity. 
         [0029]    The peptide may comprise at least 4 amino acids, for example, between 4 and 50 amino acids, or 4 and 50 amino acids, such as between 20 and 45 amino acids such as 20, 25, 30, 35, 40, 42 or 45 amino acids. 
         [0030]    In a preferred aspect of the invention, X and Y are the same and are leucine or glycine. 
         [0031]    In a further preferred aspect of the invention, X is leucine and Y is glycine. 
         [0032]    In a further preferred aspect, X and Y are the same and are lysine or arginine. Thus the invention provides peptides selected from poly-L-lysine, poly-D-lysine, poly-L-arginine and poly-D-arginine. 
         [0033]    In a yet further preferred aspect, X is lysine and Y is arginine. 
         [0034]    In the peptide of the invention 1 and m may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. 
         [0035]    In the peptide of the invention 1 may be 1, n may be 1 and m may be between 4 and 9, for example, m may be 3, 4, 5, 6, 7, 8 or 9. 
         [0036]    In the peptide of the invention 1, n and/or m may be between 1 and 5, for example, 1, 2, 3, 4 or 5. 
         [0037]    Preferably the peptide is acyclic. The peptide may be straight chained i.e. linear, or branched. 
         [0038]    The term “peptide” as used herein means, in general terms, a plurality of amino acid residues joined together by peptide bonds. It is used interchangeably and means the same as polypeptide and protein. 
         [0039]    In one embodiment of the invention, the peptide comprises an amino acid sequence selected from the group consisting of: 
         [0000]    
       
         
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
           
               
                 CGGGGGGCGGGGCGGGGGGGGGC 
                 (i)  
                 (SEQ ID NO: 1)  
               
             
          
           
               
                 GGGGGGCC 
                   
               
               
                   
               
             
          
           
               
                 CLLLLLLCLLLLCLLLLLLLLLC 
                 (ii) 
                 (SEQ ID NO: 2) 
               
             
          
           
               
                 LLLLLLCC 
                   
               
               
                   
               
             
          
           
               
                 CLGLGLGCGLGLCLGLGLGLGLC 
                 (iii) 
                 (SEQ ID NO: 3) 
               
             
          
           
               
                 GLGLGLCC 
                   
               
               
                   
               
             
          
           
               
                 CRKRKRRCRKRKCKRKRKRKRKC 
                 (iv) 
                 (SEQ ID NO: 4) 
               
             
          
           
               
                 RKRKRKCC 
                   
               
               
                   
               
               
                 KKK 
                 (v) 
               
               
                   
               
             
          
           
               
                 KKKKKKK 
                 (vi) 
                 (SEQ ID NO: 5) 
               
               
                   
               
             
          
           
               
                 RRR 
                 (vii) 
               
               
                   
               
             
          
           
               
                 RRRRRRR 
                 (viii) 
                 (SEQ ID NO: 6) 
               
             
          
         
       
     
         [0040]    In a further aspect of the invention, the peptide comprises at least one of the amino sequences (i) to (viii) and additional amino acid residues adjacent to one or both of the terminal cysteine residues. Thus, in a further embodiment of the invention there is provided a peptide comprising an amino acid sequence selected from the amino acid sequences shown in  FIG. 1  (SEQ ID NO: 7-10, referred to as Peptides 1-4, respectively). 
         [0041]    The peptides of the invention generally are synthetic peptides. The peptides may be isolated, purified peptides or variants thereof, which can be synthesized in vitro, for example, by a solid phase peptide synthetic method, by enzyme catalyzed peptide synthesis or with the aid of recombinant DNA technology. 
         [0042]    To identify active peptides that have little or no undesired toxicity for mammalian cells, individual peptides, or libraries of peptides, can be made and the individual peptides or peptides from those libraries can be screened for antimicrobial activity and toxicity, including, but not limited to, antifungal, antibacterial, antiviral, antiprotozoal, anti-parasitic activity and toxicity. 
         [0043]    The peptides of the invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the compounds. 
         [0044]    Thus, the invention encompasses the salt or pro-drug of a peptide or peptide variant of the invention. 
         [0045]    The peptides of the invention may be administered in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent peptide which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these peptides with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in  Remington&#39;s Pharmaceutical Sciences,  17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, “ Handbook of Pharmaceutical Salts Properties Selection and Use ”, Verlag Helvetica Chimica Acta and Wiley-VCH, 2002. 
         [0046]    The invention thus includes pharmaceutically-acceptable salts of the disclosed peptides wherein the parent compound is modified by making acid or base salts thereof for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glutamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. 
         [0047]    Salts of carboxyl groups of a peptide or peptide variant of the invention may be prepared in the usual manner by contacting the peptide with one or more equivalents of a desired base such as, for example, a metallic hydroxide base, e.g. sodium hydroxide; a metal carbonate or bicarbonate such as, for example, sodium carbonate or bicarbonate; or an amine base such as, for example, triethylamine, triethanolamine and the like. 
         [0048]    N-acyl derivatives of an amino group of the peptide or peptide variants of the invention may be prepared by utilizing an N-acyl protected amino acid for the final condensation, or by acylating a protected or unprotected amino acid. O-acyl derivatives may be prepared, for example, by acylation of a free hydroxy peptide or peptide resin. Either acylation may be carried out using standard acylating reagents such as acyl halides, anhydrides, acyl imidazoles, and the like. 
         [0049]    The invention includes prodrugs for the active pharmaceutical species of the described peptides, for example in which one or more functional groups are protected or derivatized but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group. The term “prodrug,” as used herein, represents in particular structures which are rapidly transformed in vivo to the parent structure, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier, 1985; and Judkins et al., Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference. 
         [0050]    Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof. Typically, such prodrugs are transformed to the active drug by hydrolysis. As examples may be mentioned the following: 
         [0000]    
       
         
               
               
             
           
               
                   
               
               
                 Functional Group 
                 Reversible derivative 
               
               
                   
               
             
             
               
                 Carboxylic acid 
                 Esters, including e.g. acyloxyalkyl esters, amides 
               
               
                 Alcohol 
                 Esters, including e.g. sulfates and phosphates as 
               
               
                   
                 well as carboxylic acid esters 
               
               
                 Amine 
                 Amides, carbamates, imines, enamines, 
               
               
                 Boronic acid 
                 Diol ester 
               
               
                 Carbonyl (aldehyde, 
                 Imines, oximes, acetals/ketals, enol esters, 
               
               
                 ketone) 
                 oxazolidines and thiazoxolidines 
               
               
                   
               
             
          
         
       
     
         [0051]    Prodrugs also include compounds convertible to the active drug by an oxidative or reductive reaction. As examples may be mentioned: 
         [0052]    Oxidative Activation
       N- and O-dealkylation   Oxidative deamination   N-oxidation   Epoxidation       
 
         [0057]    Reductive Activation
       Azo reduction   Sulfoxide reduction   Disulfide reduction   Bioreductive alkylation   Nitro reduction.       
 
         [0063]    Also to be mentioned as metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation. 
         [0064]    The use of protecting groups is fully described in “Protective Groups in Organic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 2nd edition, T W Greene &amp; P G M Wutz, Wiley-Interscience (1991). 
         [0065]    Thus, it will be appreciated by those skilled in the art that, although protected derivatives of the described peptides may not possess pharmacological activity as such, they may be administered, for example parenterally or orally, and thereafter metabolized in the body to form compounds which are pharmacologically active. Such derivatives are therefore examples of “prodrugs”. All prodrugs of the described compounds are included within the scope of the invention. 
         [0066]    A further aspect of the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of at least one of the peptides of the invention, or two or more different peptides of the invention. 
         [0067]    These peptides also include a pharmaceutically acceptable carrier, excipient or diluent. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 
         [0068]    The peptides of the invention are useful, inter alia, as antimicrobial peptides, for example, against bacteria, fungi, yeast, parasites, protozoa and viruses. The term, “antimicrobial peptide” can be used herein to define any peptide that has microbicidal and/or microbistatic activity and encompasses, non-exclusively, any peptide described as having anti-bacterial, anti-fungal, anti-mycotic, anti-parasitic, anti-protozoal, anti-viral, anti-infectious, anti-infective and/or germicidal, algicidal, amoebicidal, microbicidal, bacterici(O)dal, fungicidal, parasiticidal, protozoacidal, protozoicidal properties. 
         [0069]    Thus, the invention further provides a peptide according to the invention for use as a medicament. The peptides of the invention may have application as antimicrobial agents both in vivo and ex vivo. 
         [0070]    In a preferred aspect, the invention provides the use of a peptide according to the invention in the manufacture of a medicament for treating a microbial infection. 
         [0071]    By “microbial infection” is meant an infection caused by a bacterial, parasitic, protozoan, viral or fungal pathogen. A “pathogen” is generally defined as any disease-causing organism. A bacterial pathogen may be derived from a bacterial species selected from the group consisting of:  Staphylococcus  spp., e.g.  Staphylococcus aureus, Staphylococcus epidermidis; Enterococcus  spp., e.g.  Enterococcus faecalis; Streptococcus pyogenes; Listeria  spp.;  Pseudomonas  spp.;  Mycobacterium  spp., e.g.  Mycobacterium tuberculosis; Enterobacter  spp.;  Campylobacter  spp.;  Salmonella  spp.;  Streptococcus  spp., e.g.  Streptococcus  Group A or B,  Streptoccocus pneumoniae; Helicobacter  spp., e.g.  Helicobacter pylori; Neisseria  spp., e.g.  Neisseria gonorrhea, Neisseria meningitidis; Borrelia burgdorferi; Shigella  spp., e.g.  Shigella flexneri; Escherichia coli; Haemophilus  spp., e.g.  Haemophilus influenzae; Chlamydia  spp., e.g.  Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci; Francisella tularensis; Bacillus  spp., e.g.  Bacillus anthracia; Clostridia  spp., e.g.  Clostridium botulinum; Yersinia  spp., e.g.  Yersinia pestis; Treponema  spp.; and  Burkholderia  spp.; e.g.  Burkholderia mallei  and  Burkholderia pseudomallei.    
         [0072]    A viral pathogen may be derived from a virus selected from the group consisting of: Human Immunodeficiency Virus (HIV1 &amp; 2); Human T Cell Leukaemia Virus (HTLV 1 &amp; 2); Ebola virus; human papilloma virus (e.g. HPV-2, HPV-5, HPV-8 HPV-16, HPV-18, HPV-31, HPV-33, HPV-52, HPV-54 and HPV-56); papovavirus; rhinovirus; poliovirus; herpesvirus; adenovirus; Epstein Barr virus; influenza virus; hepatitis B and C viruses; Variola virus; rotavirus; and SARS coronavirus. 
         [0073]    A parasitic pathogen may be derived from a parasitic pathogen selected from the group consisting of  Trypanosoma  spp. ( Trypanosoma cruzi, Trypansosoma brucei ),  Leishmania  spp.,  Giardia  spp.,  Trichomonas  spp.,  Entamoeba  spp.,  Naegleria  spp.,  Acanthamoeba  spp.,  Schistosoma  spp.,  Plasmodium  spp.,  Crytosporidium  spp.,  Isospora  spp.,  Balantidium  spp.,  Loa Loa, Ascaris lumbricoides, Dirofilaria immitis , and  Toxoplasma  ssp., e.g  Toxoplasma gondii.    
         [0074]    A fungal pathogen may be derived from a fungal pathogen which is of the genus  Candida  spp., (e.g.  C. albicans ),  Epidermophyton  spp.,  Exophiala  spp.,  Microsporum  spp.,  Trichophyton  spp., (e.g  T. rubrum  and  T. interdigitale ),  Tinea  spp.,  Aspergillus  spp.,  Blastomyces  spp.,  Blastoschizomyces  spp.,  Coccidioides  spp.,  Cryptococcus  spp.,  Histoplasma  spp.,  Paracoccidiomyces  spp.,  Sporotrix  spp.,  Absidia  spp.,  Cladophialophora  spp.,  Fonsecaea  spp.,  Phialophora  spp.,  Lacazia  spp.,  Arthrographis  spp.,  Acremonium  spp.,  Actinomadura  spp.,  Apophysomyces  spp.,  Emmonsia  spp.,  Basidiobolus  spp.,  Beauveria  spp.,  Chrysosporium  spp.,  Conidiobolus  spp.,  Cunninghamella  spp.,  Fusarium  spp.,  Geotrichum  spp.,  Graphium  spp.,  Leptosphaeria  spp.,  Malassezia  spp.,  Mucor  spp.,  Neotestudina  spp.,  Nocardia  spp.,  Nocardiopsis  spp.,  Paecilomyces  spp.,  Phoma  spp.,  Piedraia  spp.,  Pneumocystis  spp.,  Pseudallescheria  spp.,  Pyrenochaeta  spp.,  Rhizomucor  spp.,  Rhizopus  spp.,  Rhodotorula  spp.,  Saccharomyces  spp.,  Scedosporium  spp.,  Scopulariopsis  spp.,  Sporobolomyces  spp.,  Syncephalastrum  spp.,  Trichoderma  spp.,  Trichosporon  spp.,  Ulocladium  spp.,  Ustilago  spp.,  Verticillium  spp. or,  Wangiella  spp. 
         [0075]    The microbial infections treatable by the peptides of the present invention may be selected from any of the human bacterial, fungal, parasitic, and enveloped viral pathogens shown in Tables 1A-D below. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
             
           
               
                 TABLE 1A 
               
             
             
               
                   
               
               
                 Non-exclusive list of Human Bacterial Pathogens 
               
             
          
           
               
                   
                 Genus 
                 Species 
                 Comments 
               
               
                   
                   
               
             
          
           
               
                   
                 
                   Abiotropha 
                 
                 
                   defectiva 
                 
               
               
                   
                   
                 
                   elegans 
                 
               
               
                   
                 
                   Achromobacter 
                 
                 
                   alcaligenes 
                 
               
               
                   
                 
                   Acidaminacoccus 
                 
                 
                   fermentans 
                 
               
               
                   
                 
                   Acinetobacter 
                 
                 
                   baumannii 
                 
               
               
                   
                   
                 
                   calcoaceticus 
                 
               
               
                   
                   
                 
                   lowffii 
                 
               
               
                   
                   
                 
                   haemolyticus 
                 
               
               
                   
                 
                   Actinobacillus 
                 
                 
                   actinomycetemcomitans 
                 
               
               
                   
                 
                   Actinomadura 
                 
                 
                   madurae 
                 
               
               
                   
                   
                 
                   pelletieri 
                 
               
               
                   
                   
                 
                   dassonvillei 
                 
               
               
                   
                 
                   Actinomyces 
                 
                 
                   israelii 
                 
               
               
                   
                   
                 
                   gerencseriae 
                 
               
               
                   
                   
                 
                   pyogenes 
                 
               
               
                   
                   
                 
                   naeslundii 
                 
               
               
                   
                   
                 
                   bernardiae 
                 
               
               
                   
                   
                 
                   neuii 
                 
               
               
                   
                   
                 
                   radingae 
                 
               
               
                   
                   
                 
                   turicensis 
                 
               
               
                   
                   
                 
                   propinicus 
                 
               
               
                   
                 
                   Aerococcus 
                 
                 
                   urinae 
                 
               
               
                   
                   
                 
                   viridans 
                 
               
               
                   
                 
                   Aeromonas 
                 
                 
                   hydrophila 
                 
               
               
                   
                   
                 
                   veroniae 
                 
               
               
                   
                   
                 
                   caviae 
                 
               
               
                   
                 
                   Alcaligenes 
                 
                 
                   xylososidans 
                 
               
               
                   
                   
                 
                   denitrificans 
                 
               
               
                   
                   
                 
                   faecalis 
                 
               
               
                   
                 
                   Anaerovibrio 
                 
                 
                   lipolytica 
                 
               
               
                   
                 
                   Arcanobacterium 
                 
                 
                   pyogenes 
                 
               
               
                   
                   
                 
                   haemolyticum 
                 
               
               
                   
                 
                   Arthrobacter 
                 
                 
                   globiformis 
                 
               
               
                   
                   
                 
                   creatinolyticus 
                 
               
               
                   
                   
                 
                   cumminsii 
                 
               
               
                   
                   
                 
                   woluwensis 
                 
               
               
                   
                 
                   Bacillus 
                 
                 
                   anthracis 
                 
               
               
                   
                   
                 
                   cereus 
                 
               
               
                   
                   
                 
                   brevis 
                 
               
               
                   
                   
                 
                   subtilis 
                 
               
               
                   
                   
                 
                   licheniformis 
                 
               
               
                   
                   
                 
                   macerans 
                 
               
               
                   
                   
                 
                   alvei 
                 
               
               
                   
                   
                 
                   megaterium 
                 
               
               
                   
                   
                 
                   pumilis 
                 
               
               
                   
                   
                 
                   coagulans 
                 
               
               
                   
                   
                 
                   laterosporus 
                 
               
               
                   
                   
                 
                   thuringiensis 
                 
               
               
                   
                   
                 
                   sphaericus 
                 
               
               
                   
                   
                 
                   circulans 
                 
               
               
                   
                 
                   Bacteroides 
                 
                 
                   fragilis 
                 
               
               
                   
                   
                 
                   vulgatus 
                 
               
               
                   
                   
                 
                   forsythus 
                 
               
               
                   
                   
                 
                   buccae 
                 
               
               
                   
                   
                 
                   gingivalis 
                 
               
               
                   
                   
                 
                   ureolyticus 
                 
               
               
                   
                   
                 
                   gracilis 
                 
               
               
                   
                   
                 
                   tectum 
                 
               
               
                   
                 
                   Bartonella 
                 
                 
                   quintana 
                 
               
               
                   
                   
                 
                   henselae 
                 
               
               
                   
                   
                 
                   bacilliformis 
                 
               
               
                   
                   
                 
                   washoensis 
                 
               
               
                   
                   
                 
                   clarridgeiae 
                 
               
               
                   
                   
                 
                   elizabethae 
                 
               
               
                   
                   Bordatella / 
                 
                   avium 
                 
               
               
                   
                 
                   Bordetella 
                 
                 
                   hinzii 
                 
               
               
                   
                   
                 
                   pertussis 
                 
               
               
                   
                   
                 
                   parapertussis 
                 
               
               
                   
                   
                 
                   bronchiseptica 
                 
               
               
                   
                   
                 
                   petrii 
                 
               
               
                   
                 
                   Borrelia 
                 
                 
                   hermsii 
                 
               
               
                   
                   
                 
                   turicatae 
                 
               
               
                   
                   
                 
                   burgdorferi 
                 
               
               
                   
                   
                 
                   recurrentis 
                 
               
               
                   
                   
                 
                   duttonii 
                 
               
               
                   
                   
                 
                   garinii 
                 
               
               
                   
                   
                 
                   afzelii 
                 
               
               
                   
                   
                 
                   japonica 
                 
               
               
                   
                   
                 
                   andersonii 
                 
               
               
                   
                 
                   Brachyspira 
                 
                 
                   hyodysenteriae 
                 
               
               
                   
                   
                 
                   pilosicoli 
                 
               
               
                   
                 
                   Brucella 
                 
                 
                   abortus 
                 
               
               
                   
                   
                 
                   melitensis 
                 
               
               
                   
                   
                 
                   suis 
                 
               
               
                   
                   
                 
                   canis 
                 
               
               
                   
                 
                   Burkholderia 
                 
                 
                   mallei 
                 
               
               
                   
                   
                 
                   cepacia 
                 
               
               
                   
                   
                 
                   pseudomallei 
                 
               
               
                   
                   
                 
                   multivorans 
                 
               
               
                   
                   
                 
                   stabilis 
                 
               
               
                   
                   
                 
                   gladioli 
                 
               
               
                   
                   
                 
                   vietnamiensis 
                 
               
               
                   
                   
                 
                   ambifaria 
                 
               
               
                   
                   
                 
                   fungorum 
                 
               
               
                   
                 
                   Calymmatobacterium 
                 
                 
                   granulomatis 
                 
               
               
                   
                 
                   Campylobacter 
                 
                 
                   fetus 
                 
               
               
                   
                   
                 
                   jejuni 
                 
               
               
                   
                   
                 
                   coli 
                 
               
               
                   
                   
                 
                   lari 
                 
               
               
                   
                   
                 
                   hyointestinalis 
                 
               
               
                   
                   
                 
                   mucosalis 
                 
               
               
                   
                   
                 
                   concisus 
                 
               
               
                   
                   
                 
                   sputorum 
                 
               
               
                   
                   
                 
                   upsaliensis 
                 
               
               
                   
                   
                 
                   curvus 
                 
               
               
                   
                   
                 
                   rectus 
                 
               
               
                   
                   
                 
                   hominis 
                 
               
               
                   
                 
                   Capnocytophaga 
                 
                 
                   canimorsus 
                 
               
               
                   
                   
                 
                   gingivalis 
                 
               
               
                   
                   
                 
                   ochracea 
                 
               
               
                   
                   
                 
                   cynodegmi 
                 
               
               
                   
                 
                   Cardiobacterium 
                 
                 
                   hominis 
                 
               
               
                   
                   
                 
                   vulvarum 
                 
               
               
                   
                 
                   Catonella 
                 
                 
                   morbi 
                 
               
               
                   
                 
                   Chlamydia 
                 
                 
                   trachomatis 
                 
               
               
                   
                   
                 
                   pneumoniae 
                 
               
               
                   
                   
                 
                   psittaci 
                 
               
               
                   
                 
                   Chryseobacterium 
                 
                 
                   meningosepticum 
                 
               
               
                   
                 
                   Citrobacter 
                 
                 
                   freundii 
                 
               
               
                   
                   
                 
                   diversus 
                 
               
               
                   
                 
                   Clostridium 
                 
                 
                   botulinum 
                 
               
               
                   
                   
                 
                   difficile 
                 
               
               
                   
                   
                 
                   tetani 
                 
               
               
                   
                   
                 
                   perfringens 
                 
               
               
                   
                   
                 
                   butyricum 
                 
               
               
                   
                   
                 
                   diphtheriae 
                 
               
               
                   
                   
                 
                   sordellii 
                 
               
               
                   
                   
                 
                   septicum 
                 
               
               
                   
                   
                 
                   tertium 
                 
               
               
                   
                   
                 
                   clostridioforme 
                 
               
               
                   
                   
                 
                   inocuum 
                 
               
               
                   
                   
                 
                   ramosum 
                 
               
               
                   
                   
                 
                   coccoides 
                 
               
               
                   
                 
                   Corynebacterium 
                 
                 
                   diphtheriae 
                 
               
               
                   
                   
                 
                   ulcerans 
                 
               
               
                   
                   
                 
                   minutissimum 
                 
               
               
                   
                   
                 
                   pseudotuberculosis 
                 
               
               
                   
                   
                 
                   pseudodiphtheriticum 
                 
               
               
                   
                   
                 
                   xerosis 
                 
               
               
                   
                   
                 
                   jeikeium 
                 
               
               
                   
                   
                 
                   parvum 
                 
               
               
                   
                   
                 
                   macginleyi 
                 
               
               
                   
                   
                 
                   amycolatum 
                 
               
               
                   
                 
                   Coxiella 
                 
                 
                   burnetii 
                 
               
               
                   
                 
                   Dermabacter 
                 
                 
                   hominis 
                 
               
               
                   
                 
                   Desulfovibrio 
                 
                 
                   desulfuricans 
                 
               
               
                   
                   
                 
                   fairfieldensis 
                 
               
               
                   
                   
                 
                   vulgaris 
                 
               
               
                   
                   
                 
                   salexigens 
                 
               
               
                   
                   
                 
                   africanus 
                 
               
               
                   
                   
                 
                   gigas 
                 
               
               
                   
                   
                 
                   baculatus 
                 
               
               
                   
                   
                 
                   sapovorans 
                 
               
               
                   
                   
                 
                   baarsii 
                 
               
               
                   
                   
                 
                   thermophilus 
                 
               
               
                   
                   
                 
                   gabonensis 
                 
               
               
                   
                   
                 
                   piger 
                 
               
               
                   
                   
                 
                   profundus 
                 
               
               
                   
                   
                 
                   aosterae 
                 
               
               
                   
                   
                 
                   burkinensis 
                 
               
               
                   
                   
                 
                   longus 
                 
               
               
                   
                   
                 
                   orale 
                 
               
               
                   
                   
                 
                   aespoeensis 
                 
               
               
                   
                 
                   Dialister 
                 
                 
                   pneumocintes 
                 
               
               
                   
                   
                 
                   invisus 
                 
               
               
                   
                 
                   Dolosicoccus 
                 
                 
                   paucivorans 
                 
               
               
                   
                 
                   Dolosigranulum 
                 
                 
                   pigrum 
                 
               
               
                   
                 
                   Edwardsiella 
                 
                 
                   tarda 
                 
               
               
                   
                   
                 
                   hoshinae 
                 
               
               
                   
                 
                   Eggerthella 
                 
                 
                   lenta 
                 
               
               
                   
                 
                   Ehrlichia 
                 
                 
                   sennetsu 
                 
               
               
                   
                   
                 
                   chaffeensis 
                 
               
               
                   
                   
                 
                   phagocytophila 
                 
               
               
                   
                   
                 
                   ewingii 
                 
               
               
                   
                   
                 
                   canis 
                 
               
               
                   
                 
                   Eikinella 
                 
                 
                   corrodens 
                 
               
               
                   
                 
                   Empedobacter 
                 
                 
                   brevis 
                 
               
               
                   
                 
                   Enterobacter 
                 
                 
                   cloacae 
                 
               
               
                   
                   
                 
                   agglomerans 
                 
               
               
                   
                   
                 
                   aerogenes 
                 
               
               
                   
                   
                 
                   sakazakii 
                 
               
               
                   
                 
                   Enterococcus 
                 
                 
                   faecalis 
                 
               
               
                   
                   
                 
                   faecium 
                 
               
               
                   
                   
                 
                   gallinarum 
                 
               
               
                   
                   
                 
                   casseliflavus 
                 
               
               
                   
                   
                 
                   flavescens 
                 
               
               
                   
                   
                 
                   gilvus 
                 
               
               
                   
                   
                 
                   hirae 
                 
               
               
                   
                   
                 
                   pallens 
                 
               
               
                   
                   
                 
                   raffinosus 
                 
               
               
                   
                   
                 
                   solitarius 
                 
               
               
                   
                 
                   Erysipelothrix 
                 
                 
                   rhusiopathiae 
                 
               
               
                   
                 
                   Escherichia 
                 
                 
                   coli 
                 
               
               
                   
                   
                 
                   fergusonii 
                 
               
               
                   
                   
                 
                   taylorae 
                 
               
               
                   
                   
                 
                   hermanii 
                 
               
               
                   
                   
                 
                   vulneris 
                 
               
               
                   
                 
                   Eubacterium 
                 
                 
                   brachy 
                 
               
               
                   
                   
                 
                   timidum 
                 
               
               
                   
                   
                 
                   nodatum 
                 
               
               
                   
                   
                 
                   saphenum 
                 
               
               
                   
                   
                 
                   aerofaciens 
                 
               
               
                   
                   
                 
                   lentum 
                 
               
               
                   
                 
                   Facklamia 
                 
                 
                   languida 
                 
               
               
                   
                   
                 
                   sourekii 
                 
               
               
                   
                   
                 
                   ignavia 
                 
               
               
                   
                   
                 
                   hominis 
                 
               
               
                   
                 
                   Filifactor 
                 
                 
                   alocis 
                 
               
               
                   
                   
                 
                   villosus 
                 
               
               
                   
                 
                   Flavimonas 
                 
                 
                   oryzihabitans 
                 
               
               
                   
                 
                   Flavobacterium 
                 
                 
                   meningosepticum 
                 
               
               
                   
                   
                 
                   breve 
                 
               
               
                   
                   
                 
                   scophthalmum 
                 
               
               
                   
                   
                 
                   johnsoniae 
                 
               
               
                   
                 
                   Fluoribacter 
                 
                 
                   bozemaniae 
                 
               
               
                   
                 
                   Francisella 
                 
                 
                   tularensis 
                 
               
               
                   
                   
                 
                   philomiragia 
                 
               
               
                   
                 
                   Fusobacterium 
                 
                 
                   necrophorum 
                 
               
               
                   
                   
                 
                   nucleatum 
                 
               
               
                   
                 
                   Gardnerella 
                 
                 
                   vaginalis 
                 
               
               
                   
                 
                   Gemella 
                 
                 
                   morbillorum 
                 
               
               
                   
                   
                 
                   haemolysans 
                 
               
               
                   
                   
                 
                   bergeriae 
                 
               
               
                   
                   
                 
                   sanguinis 
                 
               
               
                   
                 
                   Globicatella 
                 
                 
                   sanguis 
                 
               
               
                   
                   
                 
                   sanguinius 
                 
               
               
                   
                   
                 
                   sulfidifaciens 
                 
               
               
                   
                 
                   Granulicatella 
                 
                 
                   elegans 
                 
               
               
                   
                   
                 
                   adiacens 
                 
               
               
                   
                 
                   Haemophilus 
                 
                 
                   influenzae 
                 
               
               
                   
                   
                 
                   parainfluenzae 
                 
               
               
                   
                   
                 
                   ducreyi 
                 
               
               
                   
                   
                 
                   aegyptus 
                 
               
               
                   
                   
                 
                   paraphrophilus 
                 
               
               
                   
                   
                 
                   aphrophilus 
                 
               
               
                   
                 
                   Hafnia 
                 
                 
                   alvei 
                 
               
               
                   
                 
                   Helicobacter 
                 
                 
                   pylori 
                 
               
               
                   
                   
                 
                   cinaedi 
                 
               
               
                   
                   
                 
                   fennelliae 
                 
               
               
                   
                   
                 
                   rappini 
                 
               
               
                   
                   
                 
                   heilman(n)ii 
                 
               
               
                   
                   
                 
                   pullorum 
                 
               
               
                   
                   
                 
                   bilis 
                 
               
               
                   
                   
                 
                   hepaticus 
                 
               
               
                   
                   
                 
                   westmeadii 
                 
               
               
                   
                   
                 
                   canadensis 
                 
               
               
                   
                   
                 
                   typhlonius 
                 
               
               
                   
                 
                   Helococcus 
                 
                 
                   kunzii 
                 
               
               
                   
                 
                   Ignavigranum 
                 
                 
                   ruoffiae 
                 
               
               
                   
                 
                   Inquilinus 
                 
                 
                   limosus 
                 
               
               
                   
                 
                   Kingella 
                 
                 
                   kingae 
                 
               
               
                   
                   
                 
                   dentrificans 
                 
               
               
                   
                 
                   Klebsiella 
                 
                 
                   pneumoniae 
                 
               
               
                   
                   
                 
                   agglomerans 
                 
               
               
                   
                   
                 
                   oxytoca 
                 
               
               
                   
                 
                   Kytococcus 
                 
                 
                   schroeteri 
                 
               
               
                   
                 
                   Lactobacillus 
                 
                 
                   rhamnosus 
                 
               
               
                   
                 
                   Lactococcus 
                 
                 
                   lactis 
                 
               
               
                   
                 
                   Legionella 
                 
                 
                   pneumophila 
                 
               
               
                   
                   
                 
                   anisa 
                 
               
               
                   
                   
                 
                   sainthelensi 
                 
               
               
                   
                   
                 
                   birminghamensis 
                 
               
               
                   
                   
                 
                   micdadei 
                 
               
               
                   
                   
                 
                   dumofii 
                 
               
               
                   
                   
                 
                   longbeachae 
                 
               
               
                   
                   
                 
                   cincinattiensis 
                 
               
               
                   
                   
                 
                   bozemanii 
                 
               
               
                   
                   
                 
                   gormanii 
                 
               
               
                   
                   
                 
                   macehenii 
                 
               
               
                   
                   
                 
                   tusconensis 
                 
               
               
                   
                   
                 
                   feelii 
                 
               
               
                   
                   
                 
                   hackeliae 
                 
               
               
                   
                   
                 
                   oakridgensis 
                 
               
               
                   
                   
                 
                   lansingensis 
                 
               
               
                   
                   
                 
                   israelensis 
                 
               
               
                   
                   
                 
                   jordansis 
                 
               
               
                   
                   
                 
                   wadsworthii 
                 
               
               
                   
                 
                   Leptospira 
                 
                 
                   biflexa 
                 
               
               
                   
                   
                 
                   borgpetersenii 
                 
               
               
                   
                   
                 
                   interrogans 
                 
               
               
                   
                   
                 
                   kirschneri 
                 
               
               
                   
                   
                 
                   noguchii 
                 
               
               
                   
                   
                 
                   santarosai 
                 
               
               
                   
                   
                 
                   weilii 
                 
               
               
                   
                   
                 
                   wolbachii 
                 
               
               
                   
                   
                 
                   inadai 
                 
               
               
                   
                   
                 
                   meyeri 
                 
               
               
                   
                   
                 
                   ivanovii 
                 
               
               
                   
                 
                   Leptotrichia 
                 
                 
                   amnionii 
                 
               
               
                   
                   
                 
                   buccalis 
                 
               
               
                   
                   
                 
                   sanguinegans 
                 
               
               
                   
                 
                   Leuconostoc 
                 
                 
                   mesenteroides 
                 
               
               
                   
                   
                 
                   pseudomesenteroides 
                 
               
               
                   
                 
                   Listeria 
                 
                 
                   monocytogenes 
                 
               
               
                   
                   
                 
                   ivanovii 
                 
               
               
                   
                 
                   Megasphaera 
                 
                 
                   micronuciformis 
                 
               
               
                   
                   
                 
                   elsdenii 
                 
               
               
                   
                 
                   Micrococcus 
                 
                 
                   luteus 
                 
               
               
                   
                 
                   Micropolyspora 
                 
                 
                   faeni 
                 
               
               
                   
                 
                   Mobiluncus 
                 
                 
                   mulieris 
                 
               
               
                   
                   
                 
                   curtisii 
                 
               
               
                   
                 
                   Moraxella 
                 
                 
                   lacunata 
                 
               
               
                   
                   
                 
                   nonliquefaciens 
                 
               
               
                   
                   
                 
                   catarrhalis 
                 
               
               
                   
                   
                 
                   influenzae 
                 
               
               
                   
                 
                   Morganella 
                 
                 
                   morganii 
                 
               
               
                   
                 
                   Mycobacterium 
                 
                 
                   tuberculosis 
                 
               
               
                   
                   
                 
                   ulcerans 
                 
               
               
                   
                   
                 
                   avium 
                 
               
               
                   
                   
                 
                   intracellulare 
                 
               
               
                   
                   
                 
                   marin(ar)um 
                 
               
               
                   
                   
                 
                   leprae 
                 
               
               
                   
                   
                 
                   kansasii 
                 
               
               
                   
                   
                 
                   scrofulaceum 
                 
               
               
                   
                   
                 
                   chelonae 
                 
               
               
                   
                   
                 
                   bovis 
                 
               
               
                   
                   
                 
                   africanum 
                 
               
               
                   
                   
                 
                   microtii 
                 
               
               
                   
                   
                 
                   fortuitum 
                 
               
               
                   
                   
                 
                   hominis 
                 
               
               
                   
                   
                 
                   pneumoniae 
                 
               
               
                   
                   
                 
                   malmoense 
                 
               
               
                   
                   
                 
                   paratuberculosis 
                 
               
               
                   
                   
                 
                   simiae 
                 
               
               
                   
                   
                 
                   szulagi 
                 
               
               
                   
                   
                 
                   xenopi 
                 
               
               
                   
                 
                   Mycoplasma 
                 
                 
                   pneumoniae 
                 
               
               
                   
                   
                 
                   genitalium 
                 
               
               
                   
                   
                 
                   hominis 
                 
               
               
                   
                   
                 
                   pulmonis 
                 
               
               
                   
                   
                 
                   caviae 
                 
               
               
                   
                 
                   Myroides 
                 
                 
                   odoratus 
                 
               
               
                   
                   
                 
                   odoratimimus 
                 
               
               
                   
                 
                   Neisseria 
                 
                 
                   meningitides 
                 
               
               
                   
                   
                 
                   gonorrhoeae 
                 
               
               
                   
                   
                 
                   lactamica 
                 
               
               
                   
                   
                 
                   mucosa 
                 
               
               
                   
                 
                   Nocardia 
                 
                 
                   caviae 
                 
               
               
                   
                   
                 
                   asteroides 
                 
               
               
                   
                   
                 
                   brasiliensis 
                 
               
               
                   
                   
                 
                   vaccinii 
                 
               
               
                   
                   
                 
                   africana 
                 
               
               
                   
                   
                 
                   veterana 
                 
               
               
                   
                   
                 
                   arthritidis 
                 
               
               
                   
                   
                 
                   anaemiae 
                 
               
               
                   
                   
                 
                   farcinica 
                 
               
               
                   
                   
                 
                   nova 
                 
               
               
                   
                   
                 
                   otitidiscaviarum 
                 
               
               
                   
                 
                   Orientia 
                 
                 
                   tsutsugamuchi 
                 
               
               
                   
                 
                   Pandoraea 
                 
                 
                   pneumonicola 
                 
               
               
                   
                   
                 
                   sputorum 
                 
               
               
                   
                   
                 
                   apista 
                 
               
               
                   
                   
                 
                   pnomenusa 
                 
               
               
                   
                 
                   Pasteurella 
                 
                 
                   multocida 
                 
               
               
                   
                   
                 
                   pneumotrophica 
                 
               
               
                   
                   
                 
                   bettyae 
                 
               
               
                   
                   
                 
                   canis 
                 
               
               
                   
                   
                 
                   dagmatis 
                 
               
               
                   
                   
                 
                   gallinarum 
                 
               
               
                   
                   
                 
                   haemolytica 
                 
               
               
                   
                   
                 
                   stomatis 
                 
               
               
                   
                 
                   Pediococcus 
                 
                 
                   acidilactici 
                 
               
               
                   
                   
                 
                   pentosaceus 
                 
               
               
                   
                 
                   Peptostreptococcus 
                 
                 
                   magnus 
                 
               
               
                   
                   
                 
                   anaerobius 
                 
               
               
                   
                   
                 
                   micros 
                 
               
               
                   
                   
                 
                   vaginalis 
                 
               
               
                   
                   
                 
                   asaccharolyticus 
                 
               
               
                   
                   
                 
                   tetradius 
                 
               
               
                   
                   
                 
                   prevotii 
                 
               
               
                   
                 
                   Photorhabdus 
                 
                 
                   luminescens 
                 
               
               
                   
                   
                 
                   asymbiotica 
                 
               
               
                   
                 
                   Plesiomonas 
                 
                 
                   shigelloides 
                 
               
               
                   
                 ( Plesiomonas ) 
               
               
                   
                 
                   Porphyromonas 
                 
                 
                   gingivalis 
                 
               
               
                   
                   
                 
                   levii 
                 
               
               
                   
                   
                 
                   uenonsis 
                 
               
               
                   
                 
                   Prevotella 
                 
                 
                   melaninogenica 
                 
               
               
                   
                   
                 
                   intermedia 
                 
               
               
                   
                   
                 
                   bivia 
                 
               
               
                   
                   
                 
                   heparinolytica 
                 
               
               
                   
                   
                 
                   nigrescens 
                 
               
               
                   
                   
                 
                   oris 
                 
               
               
                   
                   
                 
                   disiens 
                 
               
               
                   
                 
                   Propionibacterium 
                 
                 
                   acnes 
                 
               
               
                   
                   
                 
                   propionicus 
                 
               
               
                   
                 
                   Proteus 
                 
                 
                   mirabilis 
                 
               
               
                   
                   
                 
                   vulgaris 
                 
               
               
                   
                   
                 
                   penneri 
                 
               
               
                   
                 
                   Providencia 
                 
                 
                   alcalifaciens 
                 
               
               
                   
                   
                 
                   rettgeri 
                 
               
               
                   
                   
                 
                   stuartii 
                 
               
               
                   
                 
                   Pseudomonas 
                 
                 
                   aeruginosa 
                 
               
               
                   
                   
                 
                   fluorescens 
                 
               
               
                   
                   
                 
                   putida 
                 
               
               
                   
                   
                 
                   mendonica 
                 
               
               
                   
                   
                 
                   alcaligenes 
                 
               
               
                   
                   
                 
                   pickettii 
                 
               
               
                   
                   
                 
                   maltophila 
                 
               
               
                   
                   
                 
                   cepacia 
                 
               
               
                   
                   
                 
                   mallei 
                 
               
               
                   
                   
                 
                   pseudomallei 
                 
               
               
                   
                   
                 
                   oryzihabitans 
                 
               
               
                   
                   
                 
                   stutzeri 
                 
               
               
                   
                   
                 
                   putrefaciens 
                 
               
               
                   
                 
                   Ralstonia 
                 
                 
                   picketii 
                 
               
               
                   
                   
                 
                   mannitolilytica 
                 
               
               
                   
                 
                   Rhizobium 
                 
                 
                   radiobacter 
                 
               
               
                   
                   
                 
                   massiliae 
                 
               
               
                   
                 
                   Rhodococcus 
                 
                 
                   equi 
                 
               
               
                   
                 
                   Rickettsia 
                 
                 
                   tsutsugamuchi 
                 
               
               
                   
                   
                 
                   conorii 
                 
               
               
                   
                   
                 
                   prowazekii 
                 
               
               
                   
                   
                 
                   rickettsii 
                 
               
               
                   
                   
                 
                   akari 
                 
               
               
                   
                   
                 
                   japonica 
                 
               
               
                   
                   
                 
                   austral(ens)is 
                 
               
               
                   
                   
                 
                   typhi 
                 
               
               
                   
                   
                 
                   monogolotimonae 
                 
               
               
                   
                   
                 
                   felis 
                 
               
               
                   
                   
                 
                   parkeri 
                 
               
               
                   
                   
                 
                   helvetica 
                 
               
               
                   
                   
                 
                   canada 
                 
               
               
                   
                   
                 
                   montana 
                 
               
               
                   
                   
                 
                   sennetsu 
                 
               
               
                   
                 
                   Rochalimaea 
                 
                 
                   quintana 
                 
               
               
                   
                 
                   Roseomonas 
                 
                 
                   gilardii 
                 
               
               
                   
                   
                 
                   fauriae 
                 
               
               
                   
                   
                 
                   mucosa 
                 
               
               
                   
                 
                   Rothia 
                 
                 
                   dentocariosa 
                 
               
               
                   
                 
                   Salmonella 
                 
                 
                   typhi 
                 
               
               
                   
                   
                 
                   arizonae 
                 
               
               
                   
                   
                 
                   enteritidis 
                 
               
               
                   
                   
                 
                   paratyphi 
                 
               
               
                   
                   
                 
                   typhimurium 
                 
               
               
                   
                   
                 
                   enterica 
                 
               
               
                   
                   
                 
                   dublin 
                 
               
               
                   
                   
                 
                   choleraesuis 
                 
               
               
                   
                 
                   Selenomonas 
                 
                 
                   sputagena 
                 
               
               
                   
                 
                   Serpulina 
                 
                 
                   hyodysenteriae 
                 
               
               
                   
                   
                 
                   pilosicoli 
                 
               
               
                   
                   
                 
                   murdochii 
                 
               
               
                   
                 
                   Serratia 
                 
                 
                   marcesans 
                 
               
               
                   
                   
                 
                   liquefaciens 
                 
               
               
                   
                 
                   Shigella 
                 
                 
                   flexneri 
                 
               
               
                   
                   
                 
                   boydii 
                 
               
               
                   
                   
                 
                   dysenteriae 
                 
               
               
                   
                   
                 
                   sonnei 
                 
               
               
                   
                 
                   Sneathia 
                 
                 
                   sanguinegens 
                 
               
               
                   
                 
                   Staphylococcus 
                 
                 
                   aureus 
                 
               
               
                   
                   
                 
                   epidermidis 
                 
               
               
                   
                   
                 
                   saphrophyticus 
                 
               
               
                   
                   
                 
                   lugdunensis 
                 
               
               
                   
                   
                 
                   haemolyticus 
                 
               
               
                   
                   
                 
                   warneri 
                 
               
               
                   
                   
                 
                   schleferi 
                 
               
               
                   
                   
                 
                   intermedius 
                 
               
               
                   
                 
                   Stenotrophomonas 
                 
                 
                   maltophilia 
                 
               
               
                   
                 
                   Streptobacillus 
                 
                 
                   moniliformis 
                 
               
               
                   
                 
                   Steptococcus 
                 
                 
                   pneumoniae 
                 
               
               
                   
                   
                 
                   gordonii 
                 
               
               
                   
                   
                 
                   gallolyticus 
                 
               
               
                   
                   
                 
                   pyogenes 
                 
               
               
                   
                   
                 
                   mutans 
                 
               
               
                   
                   
                 
                   sanguis 
                 
               
               
                   
                   
                 
                   iniae 
                 
               
               
                   
                   
                 
                   agalactiae 
                 
               
               
                   
                   
                 
                   faecalis 
                 
               
               
                   
                   
                 
                   suis 
                 
               
               
                   
                   
                 
                   equisimilis 
                 
               
               
                   
                   
                 
                   bovis 
                 
               
               
                   
                   
                 
                   salivarius 
                 
               
               
                   
                   
                 
                   mitis 
                 
               
               
                   
                   
                   milleri  group 
               
               
                   
                   
                 Group A, B, C, D, F, G, R 
               
               
                   
                   
                 A, β, γtype 
               
               
                   
                 
                   Streptomyces 
                 
                 
                   somaliensis 
                 
               
               
                   
                 
                   Streptophomonas 
                 
                 
                   maltophila 
                 
               
               
                   
                 
                   Thermoactinomyces 
                 
                 
                   sacchari 
                 
               
               
                   
                   
                 
                   vulgaris 
                 
               
               
                   
                   
                 
                   dichotomicus 
                 
               
               
                   
                 
                   Thermomonospora 
                 
                 
                   viridis 
                 
               
               
                   
                 
                   Treponema 
                 
                 
                   carateum 
                 
               
               
                   
                   
                 
                   pallidum 
                 
               
               
                   
                   
                 
                   pertenue 
                 
               
               
                   
                   
                 
                   denticola 
                 
               
               
                   
                 
                   Tropheryma 
                 
                 
                   whippelii 
                 
               
               
                   
                 
                   Ureaplasma 
                 
                 
                   urealyticum 
                 
               
               
                   
                   
                 
                   parvum 
                 
               
               
                   
                 
                   Vagococcus 
                 
                 
                   fluvialis 
                 
               
               
                   
                 
                   Veillonella 
                 
                 
                   montpellierensis 
                 
               
               
                   
                   
                 
                   parvula 
                 
               
               
                   
                   
                 
                   alcalescens 
                 
               
               
                   
                 
                   Weisella 
                 
                 
                   confusa 
                 
               
               
                   
                   
                 
                   cibaria 
                 
               
               
                   
                 
                   Vibrio 
                 
                 
                   cholerae 
                 
               
               
                   
                   
                 
                   parahaemolyticus 
                 
               
               
                   
                   
                 
                   vulnificus 
                 
               
               
                   
                   
                 
                   alginolyticus 
                 
               
               
                   
                   
                 
                   mimicus 
                 
               
               
                   
                   
                 
                   hollisae 
                 
               
               
                   
                   
                 
                   fluvialis 
                 
               
               
                   
                   
                 
                   damsella 
                 
               
               
                   
                   
                 
                   furnisii 
                 
               
               
                   
                   
                 
                   metchnikovii 
                 
               
               
                   
                 
                   Yersinia 
                 
                 
                   pestis 
                 
               
               
                   
                   
                 
                   enterocolitica 
                 
               
               
                   
                   
                 
                   pseudotuberculosis 
                 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 1B 
               
             
             
               
                   
               
               
                 Non-exclusive list of Human Fungal Pathogens 
               
             
          
           
               
                 Genus 
                 Species 
                 Comments 
               
               
                   
               
               
                 
                   Absidia 
                 
                 
                   corymbifera 
                 
                   
               
               
                 
                   Acremonium 
                 
                 
                   Falciforme 
                 
               
               
                   
                 
                   kiliensis 
                 
               
               
                   
                 
                   recifei 
                 
               
               
                 
                   Apophysomyces 
                 
                 
                   elegans 
                 
               
               
                 
                   Ajellomyces 
                 
                 
                   Dermatitidis 
                 
               
               
                   
                 
                   Capsulatus 
                 
               
               
                 
                   Alternaria 
                 
                 
                   alternata 
                 
               
               
                 
                   Arthroderma 
                 
                 
                   vanbreuseghemii 
                 
               
               
                 
                   Arthrographis 
                 
                 
                   kalrae 
                 
               
               
                   
                 
                   Grisea 
                 
               
               
                   
                 
                   cuboidea 
                 
               
               
                 
                   Aspergillus 
                 
                 
                   Fumigatus 
                 
               
               
                   
                 
                   Ochraceus 
                 
               
               
                   
                 
                   Versicolor 
                 
               
               
                   
                 
                   Flavus 
                 
               
               
                   
                 
                   terreus 
                 
               
               
                   
                 
                   glaucus 
                 
               
               
                   
                 
                   Nidulans 
                 
               
               
                   
                 
                   niger 
                 
               
               
                   
                 
                   Oryzae 
                 
               
               
                   
                 
                   flavatus 
                 
               
               
                   
                 
                   ustus 
                 
               
               
                 
                   Basidiobolus 
                 
                 
                   Ranarum 
                 
               
               
                   
                 
                   Meristosporus 
                 
               
               
                   
                 
                   haptosporus 
                 
               
               
                 
                   Beauveria 
                 
                 
                   bassiana 
                 
               
               
                 
                   Bipolaris 
                 
                 
                   spicifera 
                 
               
               
                   
                 
                   Australiensis 
                 
               
               
                   
                 
                   hawaiiensis 
                 
               
               
                 
                   Blastomyces 
                 
                 
                   Dermatitidis 
                 
               
               
                   
                 
                   brasiliensis 
                 
               
               
                 
                   Blastoschizomyces 
                 
                 
                   capitatum 
                 
               
               
                 
                   Candida 
                 
                 
                   Albicans 
                 
               
               
                   
                 
                   Tropicalis 
                 
               
               
                   
                 
                   Glabrata 
                 
               
               
                   
                 
                   parapsilosis 
                 
               
               
                   
                 
                   krusei 
                 
               
               
                   
                 
                   zeylanoides 
                 
               
               
                   
                 
                   guillermondii 
                 
               
               
                   
                 
                   pelliculosa 
                 
               
               
                   
                 
                   Kefyr 
                 
               
               
                   
                 
                   dubliniensis 
                 
               
               
                 
                   Chrysosporium 
                 
                 
                   Keratinophilum 
                 
               
               
                   
                 
                   Tropicum 
                 
               
               
                   
                 
                   Merdarium 
                 
               
               
                   
                 
                   Inops 
                 
               
               
                   
                 
                   Pannicola 
                 
               
               
                   
                 
                   Queenslandicum 
                 
               
               
                   
                 
                   Zonatum 
                 
               
               
                   
                 
                   parvum 
                 
               
               
                 
                   Cladophialophora 
                 
                 
                   Bantiana 
                 
               
               
                   
                 
                   carrionii 
                 
               
               
                 
                   Cladosporium 
                 
                 
                   Bantianum 
                 
               
               
                   
                 
                   Caldosporiodes 
                 
               
               
                 
                   Coccoides 
                 
                 
                   Immitis 
                 
               
               
                 
                   Conidiobolus 
                 
                 
                   coronatus 
                 
               
               
                 
                   Coniothyrium 
                 
                 
                   fuckelii 
                 
               
               
                 
                   Cryptococcus 
                 
                 
                   neoformans 
                 
                 Var  neoformans  &amp;  gattii  &amp; 
               
               
                   
                   
                 
                   grubii 
                 
               
               
                   
                 
                   Albidus 
                 
               
               
                   
                 
                   laurentii 
                 
               
               
                 
                   Cunninghamella 
                 
                 
                   bertholletiae 
                 
               
               
                 
                   Curvularia 
                 
                 
                   Brachyspora 
                 
               
               
                   
                 
                   Clavata 
                 
               
               
                   
                 
                   Geniculata 
                 
               
               
                   
                 
                   Lunata 
                 
               
               
                   
                 
                   Pallescens 
                 
               
               
                   
                 
                   Senegalensis 
                 
               
               
                   
                 
                   verruculosis 
                 
               
               
                 
                   Emmonsia 
                 
                 
                   Parva 
                 
                 Var  parva  &amp;  crescens   
               
               
                 
                   Epidermophyton 
                 
                 
                   Floccosum 
                 
               
               
                   
                 
                   rubrum 
                 
               
               
                   
                 
                   stockdaleae 
                 
               
               
                   
                 
                   gallinae 
                 
               
               
                 
                   Exophiala 
                 
                 
                   jeanselmiae 
                 
               
               
                   
                 
                   dermatitidis 
                 
               
               
                 
                   Exserohilum 
                 
                 
                   Rostratum 
                 
               
               
                   
                 
                   Halodes 
                 
               
               
                   
                 
                   meginnisii 
                 
               
               
                   
                 
                   longirostratum 
                 
               
               
                 
                   Filobasidiella 
                 
                 
                   neoformans 
                 
                 Var  neoformans  &amp;  gattii   
               
               
                 
                   Fonsecaea 
                 
                 
                   Compacta 
                 
               
               
                   
                 
                   Pedrosoi 
                 
               
               
                 
                   Fusarium 
                 
                 
                   oxyporum 
                 
               
               
                   
                 
                   solani 
                 
               
               
                 
                   Geotrichium 
                 
                 
                   candidum 
                 
               
               
                 
                   Histoplasma 
                 
                 
                   Capsulatum 
                 
                 Var  capsulatum ,  dubiosii  &amp; 
               
               
                   
                   
                 
                   farcinimosum 
                 
               
               
                 
                   Lacazia 
                 
                 
                   loboi 
                 
               
               
                 
                   Lasiodiplodia 
                 
                 
                   theobromae 
                 
               
               
                 
                   Leptosphaeria 
                 
                 
                   senegalensis 
                 
               
               
                 
                   Loboa 
                 
                 
                   loboi 
                 
               
               
                 
                   Madurella 
                 
                 
                   Grisea 
                 
               
               
                   
                 
                   mycetomatis 
                 
               
               
                 
                   Malassezia 
                 
                 
                   furfur 
                 
               
               
                 
                   Microsporum 
                 
                 
                   gypseum 
                 
               
               
                   
                 
                   Audoinii 
                 
               
               
                   
                 
                   canis 
                 
               
               
                   
                 
                   Nanum 
                 
               
               
                   
                 
                   Fulvum 
                 
               
               
                   
                 
                   ferrugineum 
                 
               
               
                   
                 
                   distortum 
                 
               
               
                 
                   Mucor 
                 
                 
                   Ramosissimus 
                 
               
               
                   
                 
                   Indicus 
                 
               
               
                   
                 
                   circinneloides 
                 
               
               
                   
                 
                   hiernalis 
                 
               
               
                 
                   Neotestudina 
                 
                 
                   Rosatii 
                 
               
               
                 
                   Nocardiopsis 
                 
                 
                   dassonvillei 
                 
               
               
                 
                   Ochroconis 
                 
                 
                   gallopava 
                 
               
               
                 
                   Onchyocola 
                 
                 
                   canadiensis 
                 
               
               
                 
                   Paecilomyces 
                 
                 
                   crustaceus 
                 
               
               
                   
                 
                   variotii 
                 
               
               
                 
                   Paracoccidiomyces 
                 
                 
                   brasiliensis 
                 
               
               
                 
                   Paracoccidioides 
                 
                 
                   Brasiliensis 
                 
               
               
                 
                   Penicillium 
                 
                 
                   Marneffei 
                 
               
               
                   
                 
                   verrucosum 
                 
               
               
                 
                   Phaeoannellomyces 
                 
                 
                   werneckii 
                 
               
               
                 
                   Phialophora 
                 
                 
                   verrucosa 
                 
               
               
                   
                 
                   Repens 
                 
               
               
                   
                 
                   parasitica 
                 
               
               
                 
                   Phoma 
                 
                 
                   Cruris-hominis 
                 
               
               
                 
                   Piedaria 
                 
                 
                   Hortae 
                 
               
               
                 
                   (Piedra) 
                 
                 ( iahortae ) 
               
               
                 
                   Pneumocystis 
                 
                 
                   carinii 
                 
               
               
                   
                   Jiroveci (i) 
               
               
                 
                   Pseudallescheria 
                 
                 
                   Boydii 
                 
               
               
                 
                   Pyrenochaeta 
                 
                 
                   romeroi 
                 
               
               
                 
                   Rhinosporidium 
                 
                 
                   seeberi 
                 
               
               
                 
                   Rhizomucor 
                 
                 
                   pusillus 
                 
               
               
                 
                   Rhizopus 
                 
                 
                   arrhizus 
                 
               
               
                 
                   Rhodotorula 
                 
                 
                   Rubra 
                 
               
               
                   
                 
                   Minuta 
                 
               
               
                   
                 
                   Glutinis 
                 
               
               
                   
                 
                   mucilaginosa 
                 
               
               
                 
                   Saccharomyces 
                 
                 
                   cerevisiae 
                 
               
               
                   
                 
                   Boulardii 
                 
               
               
                 
                   Scedosporium 
                 
                 
                   Apiospermum 
                 
               
               
                   
                 
                   Proliferans 
                 
               
               
                   
                 
                   Inflatum 
                 
               
               
                 
                   Scopulariopsis 
                 
                 
                   brevicaulis 
                 
               
               
                 
                   Schizophyllum 
                 
                 
                   commune 
                 
               
               
                 
                   Scytalidium 
                 
                 
                   Dimidiatum 
                 
               
               
                   
                 
                   hyalinum 
                 
               
               
                 
                   Sporobolomyces 
                 
                 
                   salmonicolor 
                 
               
               
                 
                   Sporothrix 
                 
                 
                   Schenckii 
                 
               
               
                 
                   Stachybotrys 
                 
                 
                   Chartarum 
                 
               
               
                   
                 
                   Atra 
                 
               
               
                   
                 
                   alternans 
                 
               
               
                 
                   Synchephalastrum 
                 
                 
                   racemosum 
                 
               
               
                 
                   Trichoderma 
                 
                 
                   longibrachiatum 
                 
               
               
                 
                   Trichophyton 
                 
                 
                   Rubrum 
                 
                 Including var  nigricans  &amp; 
               
               
                   
                   
                 granular 
               
               
                   
                 
                   Interdigitale 
                 
               
               
                   
                 
                   Mentagrophytes 
                 
                 Including var  interdigitale   
               
               
                   
                   
                 &amp;  goetzii   
               
               
                   
                 
                   Violaceum 
                 
               
               
                   
                 
                   Tonsurans 
                 
               
               
                   
                 
                   schoenleinii 
                 
               
               
                   
                 
                   Megninii 
                 
               
               
                   
                 
                   concentricum 
                 
               
               
                   
                 
                   Sourdanense 
                 
               
               
                   
                 
                   gourvilii 
                 
               
               
                   
                 
                   verrucosum 
                 
               
               
                   
                 
                   terrestre 
                 
               
               
                 
                   Trichosporon 
                 
                 
                   beigleii 
                 
               
               
                 
                   Ulocladium 
                 
                 
                   botyris 
                 
               
               
                   
                 
                   chartarum 
                 
               
               
                 
                   Ustilago 
                 
                 
                   maydis 
                 
               
               
                 
                   Verticillium 
                 
                 
                   affinae 
                 
               
               
                   
                 
                   Albo-atrum 
                 
               
               
                   
                 
                   fusisporum 
                 
               
               
                   
                 
                   luteoalbum 
                 
               
               
                 
                   Wangiella 
                 
                 
                   dermatitidis 
                 
               
               
                 
                   Xylohypha 
                 
                 
                   Bantiana 
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
             
           
               
                 TABLE 1C 
               
             
             
               
                   
               
               
                 Non-exclusive list of Human Parasitic Pathogens 
               
             
          
           
               
                   
                 Genus 
                 Species 
                 Comments 
               
               
                   
                   
               
             
          
           
               
                   
                 
                   Acanthamoeba 
                 
                 
                   castellanii 
                 
               
               
                   
                   
                 
                   culbertsoni 
                 
               
               
                   
                 
                   Ancylostoma 
                 
                 
                   duodenale 
                 
               
               
                   
                 
                   Angiostrongylus 
                 
                 
                   cantonensis 
                 
               
               
                   
                   
                 
                   costaricensis 
                 
               
               
                   
                 
                   Anisakis 
                 
                 
                   simplex 
                 
               
               
                   
                 
                   Ascaris 
                 
                 
                   lumbricoides 
                 
               
               
                   
                   
                 
                   suum 
                 
               
               
                   
                 
                   Babesia 
                 
                 
                   divergens 
                 
               
               
                   
                   
                 
                   microti 
                 
               
               
                   
                   
                 
                   Equi 
                 
               
               
                   
                 
                   Balamuthia 
                 
                 
                   mandrillaris 
                 
               
               
                   
                 
                   Balantidium 
                 
                 
                   coli 
                 
               
               
                   
                 
                   Blastocystis 
                 
                 
                   hominis 
                 
               
               
                   
                 
                   Brugia 
                 
                 
                   malayi 
                 
               
               
                   
                   
                 
                   pahangi 
                 
               
               
                   
                   
                 
                   timori 
                 
               
               
                   
                 
                   Capillaria 
                 
                 
                   philipinensis 
                 
               
               
                   
                 
                   Clonorchis 
                 
                 
                   sinensis 
                 
               
               
                   
                   
                 
                   viverrini 
                 
               
               
                   
                 
                   Contracaecum 
                 
                 
                   osculatum 
                 
               
               
                   
                 
                   Cryptosporidium 
                 
                 
                   parvum 
                 
               
               
                   
                 
                   Cyclospora 
                 
                 
                   cayetanensis 
                 
               
               
                   
                 
                   Dicrocoelium 
                 
                 
                   dendriticum 
                 
               
               
                   
                 
                   Dientamoeba 
                 
                 
                   fragilis 
                 
               
               
                   
                 
                   Diphyllobothrium 
                 
                 
                   latum 
                 
               
               
                   
                 
                   Dirofilaria 
                 
                 
                   immitis 
                 
               
               
                   
                 
                   Dracunculus 
                 
                 
                   medinensis 
                 
               
               
                   
                 
                   Echinococcus 
                 
                 
                   granulosus 
                 
               
               
                   
                   
                 
                   multilocaris 
                 
               
               
                   
                   
                 
                   vogeli 
                 
               
               
                   
                 
                   Entamoeba 
                 
                 
                   histolytica 
                 
               
               
                   
                 
                   Enterobius 
                 
                 
                   vermicularis 
                 
               
               
                   
                 
                   Enterocytozoon 
                 
                 
                   bieneusi 
                 
               
               
                   
                 
                   Fasciola 
                 
                 
                   gigantica 
                 
               
               
                   
                   
                 
                   hepatica 
                 
               
               
                   
                   
                 
                   buski 
                 
               
               
                   
                 
                   Giardia 
                 
                 
                   lamblia 
                 
               
               
                   
                   
                 
                   intestinalis 
                 
               
               
                   
                 
                   Heterophyes 
                 
               
               
                   
                 
                   Hymenolepis 
                 
                 
                   diminuta 
                 
               
               
                   
                   
                 
                   nana 
                 
               
               
                   
                 
                   Isospora 
                 
                 
                   belli 
                 
               
               
                   
                 
                   Leishmania 
                 
                 
                   aethipoica 
                 
               
               
                   
                   
                 
                   brasiliensis 
                 
               
               
                   
                   
                 
                   donovani 
                 
               
               
                   
                   
                 
                   mexicana 
                 
               
               
                   
                   
                 
                   peruviana 
                 
               
               
                   
                   
                 
                   major 
                 
               
               
                   
                   
                 
                   tropica 
                 
               
               
                   
                   
                 
                   amazonensis 
                 
               
               
                   
                   
                 
                   panamensis 
                 
               
               
                   
                   
                 
                   guyanensis 
                 
               
               
                   
                   
                 
                   infantum 
                 
               
               
                   
                   
                 
                   chagasi 
                 
               
               
                   
                 
                   Loa 
                 
                 
                   loa 
                 
               
               
                   
                 
                   Mansonella 
                 
                 
                   ozzardi 
                 
               
               
                   
                   
                 
                   perstans 
                 
               
               
                   
                   
                 
                   streptocerca 
                 
               
               
                   
                 
                   Naegleria 
                 
                 
                   fowleri 
                 
               
               
                   
                 
                   Necator 
                 
                 
                   americanus 
                 
               
               
                   
                 
                   Onchocerca 
                 
                 
                   volvulus 
                 
               
               
                   
                 
                   Opisthorcis 
                 
                 
                   felineus 
                 
               
               
                   
                   
                 
                   sinensis 
                 
               
               
                   
                   
                 
                   viverinni 
                 
               
               
                   
                 
                   Paragonimus 
                 
                 
                   westermani 
                 
               
               
                   
                 
                   Plasmodium 
                 
                 
                   falciparum 
                 
               
               
                   
                   
                 
                   vivax 
                 
               
               
                   
                   
                 
                   Malariae 
                 
               
               
                   
                   
                 
                   ovale 
                 
               
               
                   
                 
                   Pneumocystis 
                 
                 
                   carinii 
                 
               
               
                   
                 
                   Pseudoterranova 
                 
                 
                   decipiens 
                 
               
               
                   
                 
                   Rhinosporidium 
                 
                 
                   seeberi 
                 
               
               
                   
                 
                   Sarcocystis 
                 
                 
                   suihominis 
                 
               
               
                   
                 
                   Schistosoma 
                 
                 
                   haematobium 
                 
               
               
                   
                   
                 
                   intercalatum 
                 
               
               
                   
                   
                 
                   japonicum 
                 
               
               
                   
                   
                 
                   mansoni 
                 
               
               
                   
                   
                 
                   mekongi 
                 
               
               
                   
                 
                   Spirostomum 
                 
                 
                   teres 
                 
               
               
                   
                 
                   Strongyloides 
                 
                 
                   stercoralis 
                 
               
               
                   
                 
                   Taenia 
                 
                 
                   saginata 
                 
               
               
                   
                   
                 
                   solium 
                 
               
               
                   
                 
                   Theileria 
                 
                 
                   parva 
                 
               
               
                   
                 
                   Toxocara 
                 
                 
                   canis 
                 
               
               
                   
                   
                 
                   cati 
                 
               
               
                   
                 
                   Toxoplasma 
                 
                 
                   gondii 
                 
               
               
                   
                 
                   Trichinella 
                 
                 
                   native 
                 
               
               
                   
                   
                 
                   nelsoni 
                 
               
               
                   
                   
                 
                   spiralis 
                 
               
               
                   
                   
                 
                   psuedospiralis 
                 
               
               
                   
                 
                   Trichomonas 
                 
                 
                   vaginalis 
                 
               
               
                   
                 
                   Trichostrongylus 
                 
                 
                   orientalis 
                 
               
               
                   
                 
                   Trichuris 
                 
                 
                   trichiura 
                 
               
               
                   
                 
                   Trypanosoma 
                 
                 
                   cruzi 
                 
               
               
                   
                   
                 
                   brucei brucei 
                 
               
               
                   
                   
                 
                   brucei gambiense 
                 
               
               
                   
                   
                 
                   brucei rhodesiense 
                 
               
               
                   
                 
                   Wuchereria 
                 
                 
                   bancrofti 
                 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 1D 
               
             
             
               
                   
               
               
                 Non-exclusive list of Human Enveloped Viral Pathogens 
               
               
                 Enveloped virus: A virus having an outer lipoprotein bi-layer acquired 
               
               
                 by budding through the host cell membrane. 
               
             
          
           
               
                 Virus 
                 Disease 
                 Comments 
               
               
                   
               
               
                 TOGAVIRIDAE 
                   
                   
               
               
                 Alphaviruses: 
               
               
                 Eastern equine 
                 Fever, malaise, 
               
               
                 encephalomyelitis 
                 headaches, encephalitis 
               
               
                 Western equine 
                 Fever, malaise, 
               
               
                 encephalomyelitis 
                 headaches, encephalitis 
               
               
                 Venezuelan equine 
                 Fever, malaise, 
                 Includes Mucambo, 
               
               
                 encephalomyelitis 
                 headaches, encephalitis 
                 Everglades, Tonate, Pixuna, 
               
               
                   
                   
                 Cabassou virus/fever 
               
               
                 Ross river 
                 Fever, rash, arthralgia 
               
               
                 Chikungunya 
                 Fever, rash, arthralgia, 
               
               
                   
                 arthritis 
               
               
                 Mayaro 
                 Fever, rash, arthralgia 
               
               
                 O&#39;nyong&#39;nyong 
                 Fever, rash, arthralgia 
               
               
                 Sindbis 
                 Fever, rash, arthralgia 
                 Ockelbo, Karelian &amp; Pogosta 
               
               
                   
                   
                 fevers 
               
               
                 Ndumu 
               
               
                 Middleburg 
               
               
                 Bebaru 
               
               
                 Sagiyama 
               
               
                 Sem(i)liki forest 
               
               
                 Getah 
               
               
                 Rubiviridae: 
               
               
                 Rubella 
                 German Measles 
               
               
                 Flaviviruses: 
               
               
                 Yellow fever 
                 hepatitis with a 
                 high fever, chills, headache, 
               
               
                   
                 hemorrhagic diathesis 
                 muscle aches, vomiting, and 
               
               
                   
                   
                 backache, shock, bleeding, 
               
               
                   
                   
                 and kidney &amp; liver failure 
               
               
                 Dengue (types 1, 2, 3 &amp; 4) 
                 immunopathologic 
                 Dengue fever or Dengue 
               
               
                   
                 disease (shock &amp; 
                 hemorrhagic fever 
               
               
                   
                 haemorrhage) 
               
               
                 St Louis Encephalitis 
                 encephalitis 
               
               
                 Japanese Encaphalitis 
                 Encephalitis 
               
               
                 Murray Valley Encaphalitis 
                 Encephalitis 
               
               
                 Russian Spring Summer 
                 Encephalitis 
                 Tick-borne 
               
               
                 Encaphalitis 
               
               
                 Tick-borne encephalitis 
                 Encephalitis 
               
               
                 Kyanasur forest disease 
                 encephalitis 
                 Tick-borne 
               
               
                 Powassan 
                 Hemorrhagic fever 
                 Tick-borne 
               
               
                 Hepatitis C 
               
               
                 Hepatitis G 
               
               
                 Israel Turkey Meningitis 
                 Meningitis 
               
               
                 Rocio 
               
               
                 Sal Vieja 
               
               
                 San Perlita 
               
               
                 Spondweni 
               
               
                 Wesselsbron 
               
               
                 West Nile Fever 
               
               
                 Absettarov 
                   
                 Tick-borne 
               
               
                 Hanzalova 
                   
                 Tick-borne 
               
               
                 Hypr 
                   
                 Tick-borne 
               
               
                 Kumlinge 
                   
                 Tick-borne 
               
               
                 Louping ill 
                   
                 Tick-borne 
               
               
                 Negishi 
                   
                 Tick-borne 
               
               
                 Omsk 
                   
                 Tick-borne 
               
               
                 BUNYAVIRIDAE 
               
               
                 Bangui 
                 Fever, rash 
               
               
                 Bhanja 
                 Fever, encephalitis 
               
               
                 Issk-kul 
                 Fever 
               
               
                 Kasokero 
                 Fever 
               
               
                 Nyando 
                 Fever 
               
               
                 Tamdy 
                 Fever 
               
               
                 Tataguine 
                 Fever 
               
               
                 Wanowrie 
                 Fever, hemorrhage 
               
               
                 Bunyaviruses: 
               
               
                 Akabene 
               
               
                 Bunyamwera 
                 Fever 
                 Bunyamwera, Germiston, 
               
               
                   
                   
                 Ilesha, Shokwe, Tensaw, 
               
               
                   
                   
                 Wyeomyia 
               
               
                 Bwamba 
                 Fever 
                 Bwamba, Pongola 
               
               
                 C 
                 Fever 
                 Apeu, Caraparu, Itaqui, 
               
               
                   
                   
                 Madrid, Marituba, Murutucu, 
               
               
                   
                   
                 Nepuyo, Oriboca, Ossa, 
               
               
                   
                   
                 Restan 
               
               
                 California 
                 Fever &amp;/or Encephalitis 
                 California encephalitis, 
               
               
                   
                   
                 Guaroa, Inkoo, La Crosse, 
               
               
                   
                   
                 Snowshoe hare, Jamestown 
               
               
                   
                   
                 Canyon, Tahyna 
               
               
                 Guama 
                 Fever 
                 Catu, Guama 
               
               
                 Simbu 
                 Fever 
                 Shuni, Oropouche 
               
               
                 Phleboviridae: 
               
               
                 Phlebotomous fever 
                 fever 
                 Alenquer, Candinu, Chagres, 
               
               
                   
                   
                 Naples, Punto Toro, Rift 
               
               
                   
                   
                 Valley Fever, Sicilian, 
               
               
                   
                   
                 Toscana 
               
               
                 Sandfly fever 
               
               
                 Nairoviridae: 
               
               
                 Crimean-Congo 
                 Hemmorhagic fever 
               
               
                 Nairobi Sheep Disease 
                 Fever 
               
               
                 Hazara 
               
               
                 Hantaviridae: 
               
               
                 Hantaan 
                 Hemorrhagic fever with 
                 Hantaan (Korean 
               
               
                   
                 renal syndrome or 
                 haemorrhagic fever), 
               
               
                   
                 Hantavirus Pulmonary 
                 Puumala, Seoul, Sin Nombre 
               
               
                   
                 Syndrome 
                 (Muerto Canyon), New 
               
               
                   
                   
                 York, Black Creek Canal 
               
               
                 Belgrade (Dobrava) 
               
               
                 Prospect Hill 
               
               
                 ARENAVIRIDAE 
               
               
                 LCM-Lassa-virus-complex 
                   
                 Ippy, Lassa Fever, 
               
               
                 (Old World Arenaviruses) 
                   
                 Lymphotic choriomeningitis, 
               
               
                   
                   
                 Mobala, Mobeia 
               
               
                 Tacaribe-virus-complex 
                   
                 Ampari, Flexal, Guanarito, 
               
               
                   
                   
                 Junin, Latino, Machupo, 
               
               
                   
                   
                 Parana, Pichinde, Sabia, 
               
               
                   
                   
                 Tamiami 
               
               
                 ORTHOMYXOVIRIDAE 
               
               
                 Influenza 
                   
                 Types A, B &amp; C 
               
               
                 Dhori 
                   
                 Tick-borne 
               
               
                 Thogoto 
                   
                 Tick-borne 
               
               
                 PARAMYXOVIRIDAE 
               
               
                 Rubulavirus 
                   
                 Newcastle Disease 
               
               
                 Nipah 
               
               
                 Hendra 
                   
                 Equine morbillivirus 
               
               
                 Human metapneumonovirus 
               
               
                 Paramyxovirus: 
               
               
                 Mumps 
               
               
                 Parainfluenza 
                 mild, febrile common 
                 Types 1-4 (4 is sub-divided 
               
               
                   
                 cold to severe, 
                 into A &amp; B) 
               
               
                   
                 potentially life- 
               
               
                   
                 threatening croup, 
               
               
                   
                 bronchiolitis, and 
               
               
                   
                 pneumonia 
               
               
                 Pneumovirus: 
               
               
                 Respiratory Synctial Virus 
                   
                 Types A &amp; B 
               
               
                 Morbillivirus: 
               
               
                 Measles 
               
               
                 CORONAVIRIDAE 
               
               
                 Coronavirus 
                 Cold 
               
               
                 SARS 
                 Severe acute respiratory 
               
               
                   
                 syndrome 
               
               
                 RHABDOVIRIDAE 
               
               
                 Piry 
               
               
                 Lyssaviridae: 
               
               
                 Rabies 
                 Rabies 
               
               
                 Lagos Bat 
               
               
                 Mogola 
               
               
                 Duvenhage 
               
               
                 European Bat Lyssavirus 
               
               
                 Vesiculovirus: 
               
               
                 Vesiculovirus 
                 Vesicular Stomatitis 
                 Types 1-4 
               
               
                 RETROVIRIDAE 
               
               
                 Oncoviridae: 
               
               
                 Human T-cell Leukaemia 
                 lymphoproliferative and 
                 Types 1, 2 &amp; 5 
               
               
                   
                 neurologic disorders 
               
               
                 Kaposi&#39;s sarcoma-associated 
               
               
                 herpesvirus 
               
               
                 Lentiviridae: 
               
               
                 Human Immunodeficiency 
                 AIDS 
                 Types 1 &amp; 2 
               
               
                 Virus 
               
               
                 Simian Immunodeficiency 
               
               
                 Virus 
               
               
                 Spumaviridae: 
               
               
                 Human Foamy Virus 
               
               
                 HERPESVIRIDAE 
               
               
                 Herpes simplex 
                 Genital &amp; oral herpes 
                 Types 1 &amp; 2 
               
               
                 Varicella-zoster virus 
                 Chicken Pox 
               
               
                 Cytomegalovirus 
                 hepatosplenomegaly, 
               
               
                   
                 retinitis, rash, and 
               
               
                   
                 central nervous system 
               
               
                   
                 involvement &amp; possibly 
               
               
                   
                 mononucleosis 
               
               
                 Epstein-Barr virus 
                 Mononucleosis 
               
               
                 Human herpesvirus 
                 exanthem subitem 
                 Types 6 &amp; 7 
               
               
                   
                 (roseola) 
               
               
                 Kaposi&#39;s Sarcoma virus 
                 Kaposi&#39;s sarcoma 
                 Human herpesvirus type 8 
               
               
                 B virus 
                 encephalitis 
               
               
                 FILOVIRIDAE 
               
               
                 Ebola Reston 
                 multiple hemorrhagic 
               
               
                   
                 manifestations, marked 
               
               
                   
                 hepatic involvement, 
               
               
                   
                 disseminated 
               
               
                   
                 intravascular 
               
               
                   
                 coagulation, and shock 
               
               
                 Ebola Siena 
               
               
                 Ebola Sudan 
               
               
                 Ebola Zaire 
               
               
                 Marburg 
               
               
                   
               
             
          
         
       
     
         [0076]    Thus the invention provides the use of a peptide according to the invention in the manufacture of a medicament for treating a microbial infection wherein the microbial infection is a systemic, topical, subcutaneous, cutaneous or mucosal fungal infection. 
         [0077]    Fungal infections can be classified as systemic, meaning that the infection is deep and affects internal organs, blood borne, or topical (dermatophytic), meaning that the infection is superficial and occurs on the skin. Additionally, yeast infections can affect the mucous membranes of the body. Yeast infections can also be systemic (e.g. candidaemia and other frequently fatal conditions). Fungal infections on the skin are usually treated with creams or ointments (topical antifungal drugs). However, systemic infections, yeast infections or topical infections that do not clear up after treatment with creams or ointments may need to be treated with systemic antifungal drugs (oral or IV). These drugs are used, for example, to treat common fungal infections such as tinea (ringworm), which occurs on the skin or candidiasis (a yeast infection, also known as thrush), which can occur in the throat, in the vagina, or in other parts of the body. Systemic antifungal drugs are also used to treat other deep fungal infections such as histoplasmosis, blastomycosis, and aspergillosis, which can affect the lungs and other organs. They are sometimes used to prevent or treat fungal infections in people whose immune systems are weakened, such as bone marrow or organ transplant patients and people with HIV-AIDS. 
         [0078]    Topical or dermatophytic fungal infections, while not typically causative of death or of serious illness, are prevalent and are economically important because they can be expensive to treat. Topical or superficial fungal infections may include those of the skin, lamina, stratum corneum, nails and hair. Cutaneous infections are infections of the skin, finger nails and toenails. 
         [0079]    In a preferred aspect of the invention, the fungal infection is onychomycosis. Onychomycosis may be caused by a fungus from, but not limited to, the genus  Trichophyton  spp., for example, the fungus may be  Trichophyton interdigitale  or  Trichophyton rubrum.    
         [0080]    The term “onychomycosis” includes, but is not limited to, distal lateral subungual, superficial white, proximal white subungual, secondary dystrophic, primary dystrophic, endonyx, candidal (e.g. onycholysis &amp; chronic mucocutaneous disease) types of onychomycosis. Onychomycosis has been shown as a significant risk factor for more serious clinical complications, such as acute bacterial cellulitis of the arm/leg and other secondary bacterial infections, thus the present invention encompasses the treatment of these infections. 
         [0081]    The peptides of the invention are potent antimicrobial peptides for a wide variety of pathogenic organisms. However, the peptides of the invention may also be useful in the treatment of other conditions including, but not limited to, cystic fibrosis and other conditions associated with mucosal infections, for example, gastrointestinal, urogenital or respiratory infections. 
         [0082]    The peptides of the invention may also be useful in the treatment or prevention of, inter alia, wounds, ulcers and lesions for example, cutaneous wounds such cuts or burns, and conditions associated therewith. 
         [0083]    The term “treatment” relates to the effects of the peptides described herein that in imparting a benefit to patients afflicted with an (infectious) disease, including an improvement in the condition of the patient or delay in disease progression. 
         [0084]    As used herein “treatment of a wound” may include wound healing and associated conditions and therapy which promotes, augments, or accelerates healing of tissues and includes post-operative scarring, burns, psoriasis, acceleration of tissue remodelling, for example, post cosmetic surgery and organ transplantation. 
         [0085]    Thus, in a further aspect of the invention there is provided a substrate to which a peptide of the invention is applied or attached. Preferably, the substrate is suitable for application to wounds or delivery to wound sites. Preferably, the substrate allows for the transfer of the peptides of the invention from the substrate to a wound bed to achieve their antibiotic effect. The substrate may be a dressing, for example, wound dressing. The dressing may comprise a fabric material or it may be a collagen-like material. 
         [0086]    The peptides of the invention may also find application as/in a disinfectant. In this context, the peptide or pharmaceutical compositions of the invention may be applied, either alone or in combination with other disinfecting agents, to a surface to be treated. As used herein a “surface to be treated” may be a substrate as defined herein or a medical device. 
         [0087]    In a further aspect, the invention provides a method of treating or preventing a microbial infection in a subject comprising administering to said subject a therapeutically effective amount of a peptide according to the invention. 
         [0088]    In a preferred method of the invention, the microbial infection is a fungal infection. In the method of the invention the peptide may be applied to the skin or nails of said subject. 
         [0089]    Mammals, birds and other animals may be treated by the peptides, compositions or methods described herein. Such mammals and birds include humans, dogs, cats and livestock, such as horses, cattle, sheep, goats, chickens and turkeys and the like. Moreover, plants may also be treated by the peptides, compositions or methods of the invention. 
         [0090]    Where the subject is an animal, the method of the invention may be applied nail-like features, including, but not exclusive to, hooves, claws and trotters. 
         [0091]    The method of the invention may include, in addition to peptide treatment, treatments that may enhance peptide permeation into the nail. This could be facilitated by chemical or physical means. Physical treatments, such as nail etching or filing of the dorsal layer of the nail may enhance permeability of the peptides of the invention. Chemical enhancement of nail permeability to the peptides of the invention may be achieved by breaking physical or chemical bonds within the nail plate keratin. Nail softening agents, including, but not exclusive to, urea and salicylic acid, increase hydration of the nail to decrease nail density and, therefore, may increase permeability to the peptides of the invention. Compounds containing sulfhydryl groups will cleave the disulphide bonds in nail keratin, and may lead to destabilization and increased permeability of drugs. Compounds including, but not exclusive to acetylcysteine and mercaptoethanol derivatives may be used in combination with our peptides. Other known nail permeability excipients/adjuvants that may be used in combination with the peptides of the invention include methylsulfonylmethane, urea, polyethylene glycol, N-(-2-mercaptopropionyl)glycine, dimethylsulfone and 2-n-nonyl-1,3-dioxolane. 
         [0092]    In a further aspect, the invention provides a method of treating a wound in a subject comprising applying to the wound a therapeutically effective amount of a peptide, or a substrate, according to the invention. 
         [0093]    The peptides of the invention, including their salts, are administered so as to achieve a reduction in at least one symptom associated with an infection, indication or disease, or a decrease in the amount of antibody associated with the indication or disease. 
         [0094]    To achieve the desired effect(s), the peptide, a variant thereof or a combination thereof, may be administered as single or divided dosages, for example, of at least about 0.01 mg/kg to about 500 to 750 mg/kg, of at least about 0.01 mg/kg to about 300 to 500 mg/kg, at least about 0.1 mg/kg to about 100 to 300 mg/kg or at least about 1 mg/kg to about 50 to 100 mg/kg of body weight or at least about 1 mg/kg to about 20 mg/kg of body weight, although other dosages may provide beneficial results. The amount administered will vary depending on various factors including, but not limited to, the peptide chosen and its clinical effects, the disease, the weight, the physical condition, the health, the age of the mammal, whether prevention or treatment is to be achieved, and if the peptide is chemically modified. Such factors can be readily determined by the clinician examining the empirical data from the clinical trials and examining the preclinical animal model results or other test systems that are available in the art. 
         [0095]    Administration of the therapeutic agents in accordance with the present invention may be in a single dose, in multiple doses, in a continuous or intermittent manner, depending, for example, upon the recipient&#39;s physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of the peptides of the invention may be essentially continuous over a pre-selected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated. 
         [0096]    To prepare the composition, peptides are synthesized or otherwise obtained, purified as necessary or desired, and then lyophilized and stabilized. The peptide can then be adjusted to the appropriate concentration and optionally combined with other agents. The absolute weight of a given peptide included in a unit dose can vary widely. For example, about 0.01 to about 2 g or about 0.01 to about 500 mg, of at least one peptide of the invention, or a plurality of peptides specific for a particular cell type can be administered. Alternatively, the unit dosage can vary from about 0.01 g to about 50 g, from about 0.01 g to about 35 g, from about 0.1 g to about 25 g, from about 0.5 g to about 12 g, from about 0.5 g to about 8 g, from about 0.5 g to about 4 g, or from about 0.5 g to about 2 g. 
         [0097]    Daily doses of the peptides of the invention can vary as well. Such daily doses can range, for example, from about 0.001 g/day to about 100 or 50 g/day, from about 0.1 g/day to about 25 g/day, from about 0.1 g/day to about 12 g/day, from about 0.1 g/day to about 5 g/day, from about 0.1 g/day to about 2.5 g/day, from about 0.1 g/day to about 2 g/day, from about 0.5 g/day to about 8 g/day, from about 0.5 g/day to about 4 g/day, from about 0.5 g/day to about 2 g/day, and from about 0.5 g/day to about 1 g/day. 
         [0098]    Thus, one or more suitable unit dosage forms comprising the therapeutic peptides of the invention can be administered by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), rectal, dermal, transdermal, intrathoracic, intrapulmonary and intranasal (respiratory) routes. The therapeutic peptides may also be formulated in a lipid formulation or for sustained release (for example, using microencapsulation, see WO 94/07529, and U.S. Pat. No. 4,962,091). The formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well-known to the pharmaceutical arts. Such methods may include the step of mixing the therapeutic agent with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system. 
         [0099]    When the therapeutic peptides of the invention are prepared for oral administration, they are generally combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form. For oral administration, the peptides may be present as a powder, a granular formation, a solution, a suspension, an emulsion or in a natural or synthetic polymer or resin for ingestion of the active ingredients from a chewing gum. The active peptides may also be presented as a bolus, electuary or paste. Orally administered therapeutic peptides of the invention can also be formulated for sustained release, e.g., the peptides can be coated, micro-encapsulated, or otherwise placed within a sustained delivery device. The total active ingredients in such formulations comprise from 0.1 to 99.9% by weight of the formulation. 
         [0100]    Pharmaceutical formulations containing the therapeutic peptides of the invention can be prepared by procedures known in the art using well-known and readily available ingredients. For example, the peptide can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, solutions, suspensions, powders, aerosols and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include buffers, as well as fillers and extenders such as starch, cellulose, sugars, mannitol, and silicic derivatives. Binding agents can also be included such as carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose and other cellulose derivatives, alginates, gelatine, and polyvinyl-pyrrolidone. Moisturizing agents can be included such as glycerol, disintegrating agents such as calcium carbonate and sodium bicarbonate. Agents for retarding dissolution can also be included such as paraffin. Resorption accelerators such as quaternary ammonium compounds can also be included. Surface active agents such as cetyl alcohol and glycerol monostearate can be included. Adsorptive carriers such as kaolin and bentonite can be added. Lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols can also be included. Preservatives may also be added. The compositions of the invention can also contain thickening agents such as cellulose and/or cellulose derivatives. They may also contain gums such as xanthan, guar or carbo gum or gum arabic, or alternatively polyethylene glycols, bentones and montmorillonites, and the like. 
         [0101]    For example, tablets or caplets containing the peptides of the invention can include buffering agents such as calcium carbonate, magnesium oxide and magnesium carbonate. Suitable buffering agents may also include acetic acid in a salt, citric acid in a salt, boric acid in a salt and phosphoric acid in a salt. Caplets and tablets can also include inactive ingredients such as cellulose, pregelatinized starch, silicon dioxide, hydroxyl propyl methyl cellulose, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide, benzoic acid, citric acid, corn starch, mineral oil, polypropylene glycol, sodium phosphate, zinc stearate, and the like. Hard or soft gelatin capsules containing at least one peptide of the invention can contain inactive ingredients such as gelatin, microcrystalline cellulose, sodium lauryl sulfate, starch, talc, and titanium dioxide, and the like, as well as liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil. Moreover, enteric-coated caplets or tablets containing one or more peptides of the invention are designed to resist disintegration in the stomach and dissolve in the more neutral to alkaline environment of the duodenum. 
         [0102]    The therapeutic peptides of the invention can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous, intraperitoneal or intravenous routes. The pharmaceutical formulations of the therapeutic peptides of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension or salve. 
         [0103]    Thus, the therapeutic peptides may be formulated for parenteral administration (e.g. by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion containers or in multi-dose containers. As noted above, preservatives can be added to help maintain the shelve life of the dosage form. The active peptides and other ingredients may form suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active peptides and other ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water before use. 
         [0104]    These formulations can contain pharmaceutically acceptable carriers, vehicles and adjuvants that are well-known in the art. It is possible, for example, to prepare solutions using one or more organic solvent(s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvents such as acetone, acetic acid, ethanol, isopropyl alcohol, dimethyl sulfoxide, glycol ethers such as the products sold under the name “Dowanol”, polyglycols and polyethylene glycols, C 1 -C 4  alkyl esters of short-chain acids, ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the name “Miglyol”, isopropyl mytrisate, animal, mineral and vegetable oils and polysiloxanes. 
         [0105]    Preferably, the pharmaceutical formulations of the therapeutic peptides of the invention can also take the form of a solvent or diluent comprising the peptide. Solvents or diluents may include acid solutions, dimethylsulphone, N-(2-mercaptopropionyl) glycine, 2-n-nonyl-1,3-dioxolane and ethyl alcohol. Preferably the solvent/diluent is an acidic solvent, for example, acetic acid, citric acid, boric acid, lactic acid, propionic acid, phosphoric acid, benzoic acid, butyric acid, malic acid, malonic acid, oxalic acid, succinic acid or tartaric acid. 
         [0106]    More preferably, the solvent is an acetic acid solution. The solvent, for example acetic acid solution, may be present in the composition at a concentration of less than 1%, 0.5%, 0.25%, 0.1%, 0.05% or 0.01% acid. 
         [0107]    In a further aspect of the present invention there is provided the use of an acid in the manufacture of a medicament for treating a microbial infection, in particular a fungal infection. The fungal infection may be onychomycosis. Onychomycosis may be caused by a fungus from, but not limited to the genus  Trichophyton  spp., for example, the fungus may be  Trichophyton interdigitale  or  Trichophyton rubrum . The acid may be as hereinbefore described. Preferably the acid is acetic acid. Preferably still the acid is provided in solution at a concentration of less than 1%, 0.5%, 0.25%, 0.1%, 0.05% or 0.01% acid, for example acetic acid. Typically the medicament is adapted for topical administration for treatment of, for example, nails. 
         [0108]    As used hereinafter, the term “active agent” encompasses a single peptide according to the invention, or a combination of peptides as described herein. The term “active agent” may also encompass a pharmaceutically effective amount of an acid as herein described. The active agents may be administered simultaneously, sequentially or separately. It is generally preferred that such administration be topical. 
         [0109]    The active agents may be administered in synergistically effective amounts. The invention therefore includes: the use of synergistically effective amounts of the active agents, for example a peptide according to the invention and a pharmaceutically effective amount of an acid as herein described, for the manufacture of a product, e.g. a medicament, for simultaneous, separate or sequential administration of said agents in the treatment of a microbial infection. 
         [0110]    It is possible to add, if necessary, an adjuvant chosen from antioxidants, surfactants, other preservatives, film-forming, keratolytic or comedolytic agents, perfumes, flavorings and colorings. Antioxidants such as t-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene and α-tocopherol and its derivates can be added. 
         [0111]    Also contemplated are combination products that include one or more peptides of the present invention and one or more other antimicrobial or antifungal agents, for example, polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin, azoles and triazoles such as voriconazole, fluconazole, ketoconazole, itraconazole, pozaconazole and the like; glucan synthase inhibitors such as caspofungin, micafungin (FK463), and V-echinocandin (LY303366); griseofulvin; allylamines such as terbinafine; flucytosine or other antifungal agents, including those described herein. In addition, it is contemplated that the peptides might be combined with topical antifungal agents such as ciclopirox olamine, haloprogin, tolnaftate, undecylenate, topical nysatin, amorolfine, butenafine, naftifine, terbinafine, and other topical agents. 
         [0112]    Additionally, the peptides are well suited to formulation as sustained release dosage forms and the like. The formulations can be so constituted that they release the active peptide, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time. Coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide-glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g. stents, catheters, peritoneal dialysis tubing, draining devices and the like. 
         [0113]    For topical administration, the active agents may be formulated as is known in the art for direct application to a target area. Forms chiefly conditioned for topical application take the form, for example, of creams, milks, gels, powders, dispersion or microemulsions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, aerosol formulations (e.g. sprays or foams), soaps, detergents, lotions or cakes of soap. Other conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, creams, lotions, pastes, jellies, sprays, and aerosols. Thus, the therapeutic peptides of the invention can be delivered via patches or bandages for dermal administration. Alternatively, the peptide can be formulated to be part of an adhesive polymer, such as polyacrylate or acrylate/vinyl acetate copolymer. For long-term applications it might be desirable to use microporous and/or breathable backing laminates, so hydration or maceration of the skin can be minimized. The backing layer can be any appropriate thickness that will provide the desired protective and support functions. A suitable thickness will generally be from about 10 to about 200 microns. 
         [0114]    Topical administration may be in the form of a nail coating or lacquer. For example, the antifungal peptides can be formulated in a solution for topical administration that contains ethyle acetate (NF), isopropyl alcohol (USP), and butyl monoester of poly[methylvinyl ether/maleic acid] in isopropyl alcohol. 
         [0115]    Pharmaceutical formulations for topical administration may comprise, for example, a physiologically acceptable buffered saline solution containing between about 0.001 mg/ml and about 100 mg/ml, for example between 0.1 mg/ml and 10 mg/ml, of one or more of the peptides of the present invention specific for the indication or disease to be treated. 
         [0116]    Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The active peptides can also be delivered via iontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122; 4,383,529; or 4,051,842. The percentage by weight of a therapeutic agent of the invention present in a topical formulation will depend on various factors, but generally will be from 0.01% to 95% of the total weight of the formulation, and typically 0.1-85% by weight. 
         [0117]    Drops, such as eye drops or nose drops, may be formulated with one or more of the therapeutic peptides in an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Liquid sprays can be pumped, or are conveniently delivered from pressurized packs. Drops can be delivered via a simple eye dropper-capped bottle, via a plastic bottle adapted to deliver liquid contents drop-wise, or via a specially shaped closure. 
         [0118]    The therapeutic peptide may further be formulated for topical administration in the mouth or throat. For example, the active ingredients may be formulated as a lozenge further comprising a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the composition in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the composition of the present invention in a suitable liquid carrier. 
         [0119]    The pharmaceutical formulations of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of the type that are available in the art. Examples of such substances include normal saline solutions such as physiologically buffered saline solutions and water. Specific non-limiting examples of the carriers and/or diluents that are useful in the pharmaceutical formulations of the present invention include water and physiologically acceptable buffered saline solutions such as phosphate buffered saline solutions pH 7.0-8.0. 
         [0120]    The peptides of the invention can also be administered to the respiratory tract. Thus, the present invention also provides aerosol pharmaceutical formulations and dosage forms for use in the methods of the invention. In general, such dosage forms comprise an amount of at least one of the agents of the invention effective to treat or prevent the clinical symptoms of a specific infection, indication or disease. Any statistically significant attenuation of one or more symptoms of an infection, indication or disease that has been treated pursuant to the method of the present invention is considered to be a treatment of such infection, indication or disease within the scope of the invention. 
         [0121]    Alternatively, for administration by inhalation or insufflation, the composition may take the form of a dry powder, for example, a powder mix of the therapeutic agent and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges, or, e.g. gelatine or blister packs from which the powder may be administered with the aid of an inhalator, insufflator, or a metered-dose inhaler (see, for example, the pressurized metered dose inhaler (MDI) and the dry powder inhaler disclosed in Newinan, S. P. in  Aerosols and the Lung , Clarke, S. W. and Davia, D. eds., pp. 197-224, Butterworths, London, England, 1984). 
         [0122]    Therapeutic peptides of the present invention can also be administered in an aqueous solution when administered in an aerosol or inhaled form. Thus, other aerosol pharmaceutical formulations may comprise, for example, a physiologically acceptable buffered saline solution containing between about 0.001 mg/ml and about 100 mg/ml of one or more of the peptides of the present invention specific for the indication or disease to be treated. Dry aerosol in the form of finely divided solid peptide or nucleic acid particles that are not dissolved or suspended in a liquid are also useful in the practice of the present invention. Peptides of the present invention may be formulated as dusting powders and comprise finely divided particles having an average particle size of between about 1 and 5 μm, alternatively between 2 and 3 μm. Finely divided particles may be prepared by pulverization and screen filtration using techniques well-known in the art. The particles may be administered by inhaling a predetermined quantity of the finely divided material, which can be in the form of a powder. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular infection, indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units. Moreover, the effective amount may be achieved using less than the dose in the dosage form, either individually, or in a series of administrations. 
         [0123]    For administration to the upper (nasal) or lower respiratory tract by inhalation, the therapeutic peptides of the invention are conveniently delivered from a nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Nebulizers include, but are not limited to, those described in U.S. Pat. Nos. 4,624,251; 3,703,173; 3,561,444; and 4,635,627. Aerosol delivery systems of the type disclosed herein are available from numerous commercial sources including Fisons Corporation (Bedford, Mass.), Schering Corp. (Kenilworth, N.J.) and American Pharmoseal Co. (Valencia, Calif.). For intra-nasal administration, the therapeutic agent may also be administered via nose drops, a liquid spray, such as via a plastic bottle atomizer or metered-dose inhaler. Typical of atomizers are the Mistometer (Wintrop) and the Medihaler (Riker). 
         [0124]    Furthermore, the active ingredients may also be used in combination with other therapeutic agents, for example, pain relievers, anti-inflammatory agents, antihistamines, bronchodilators and the like, whether for the conditions described or some other condition. 
         [0125]    The present invention also provides a screening assay for peptides that have low toxicity for normal human or other animal cells but have desirable antimicrobial, e.g. antifungal, properties (permeabilizing fungal cell membranes, lysing or otherwise killing or inhibiting the growth of fungi). 
         [0126]    Candidate peptides may be obtained from libraries of the peptides of the invention as described herein. The peptides can also be individually or rationally designed to have specific structural features. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0127]    The invention will now be described by way of Example only with reference to the following figures wherein: 
           [0128]      FIG. 1  shows the amino acid sequences of four peptides according to the invention (SEQ ID NO: 7-10, referred to as Peptides 1-4, respectively); 
           [0129]      FIG. 2  is a histogram demonstrating the growth of the fungus,  T. interdigitale  after (a) 4 days and (b) 7 days of treatment with the peptides of  FIG. 1 ; 
           [0130]      FIG. 3  is a histogram demonstrating the growth of the fungus,  T. rubrum  after (a) 4 days and (b) 7 days of treatment with the peptides of  FIG. 1 ; 
           [0131]      FIG. 4  is a histogram demonstrating the growth of the fungus,  Candida albicans , after (a) 24 hours and (b) 48 hours of treatment with the peptides of  FIG. 1 ; 
           [0132]      FIG. 5  is a histogram showing the results of a dose-response experiment for peptide 1 (shown in  FIG. 1 ) on the growth of  Candida albicans  after a 24 hour treatment; 
           [0133]      FIG. 6  is a graph showing  Candida  spp. survival at 24 hours in the presence of a range of doses of peptide 4 as shown in  FIG. 1 ; 
           [0134]      FIG. 7  is a graph showing the survival of 3 different strains of bacteria at 24 hours in the presence of a range of doses of peptide 4 as shown in  FIG. 1 ; 
           [0135]      FIG. 8  is a histogram demonstrating the synergistic impact of 0.01% acetic acid on the antifungal activity (against  T. rubrum ) of peptide 4 (1 mg/ml) at day 3 of growth; 
           [0136]      FIG. 9  is a histogram demonstrating the inhibition of  T. interdigitale  and  T. rubrum  by peptide 4; 
           [0137]      FIG. 10  is a histogram showing the effects of Peptide 3 and 4 on  T. interdigitale;    
           [0138]      FIG. 11  is a histogram showing the effect of acetic acid on growth of  T. interdigitale;    
           [0139]      FIG. 12  is a histogram showing the effect of polylysine on  T. interdigitale  growth; 
           [0140]      FIG. 13  is a histogram showing the effects of polylysine and polyarginine on the growth of  T. rubrum;    
           [0141]      FIG. 14  is a histogram showing the inhibition of  T. interdigitale  and  T. rubrum  by poly-L-arginine; 
           [0142]      FIG. 15  is a histogram showing the effect of a reduced concentration of polyarginine on  T. rubrum  and  T. interdigitale;    
           [0143]      FIG. 16  is a histogram showing the effect of trimers on the growth of  T. rubrum;    
           [0144]      FIG. 17  is a histogram showing the effect of Peptide 4 and NaCl on the growth of  T. interdigitale;    
           [0145]      FIG. 18  is a graph showing the effect of Peptide 4 on  Candida albicans  at increased salt concentrations; and 
           [0146]      FIG. 19  is a histogram showing the effects of polylysine and polyarginine on the survival of  Candida albicans.    
       
    
    
     DETAILED DESCRIPTION 
       [0147]    The invention will now be described by way of reference only to the following examples. 
       EXAMPLES 
     Materials and Methods 
       [0148]    All peptides were produced either by solid-phase synthesis under contract by Invitrogen-Evoquest, Carlsbad, Calif., USA or were obtained from a peptide supplier NeoMPS SA (Strasbourg, France) or Sigma-Aldrich Chemical Company Ltd. (Poole, UK). For tests with fungi, lyophilized peptide was prepared as a stock solution of 1,000 μg/ml in assay buffer. Where explicitly stated in experiments from which  FIGS. 2-8  and  FIG. 11  were generated, acetic acid was added as a solvent to a final concentration of 0.5%. 
       Pathogens 
       [0149]      Trichophyton interdigitale  (NCPF 117) and  Trichophyton rubrum  (NCPF 335) strains were obtained from the National Collection of Pathogenic Fungi, Bristol and maintained in culture by transfer at approximately monthly intervals on slopes of Sabuoraud&#39;s agar and Potato Dextrose Agar at 30° C.  Candida albicans  strain 3179 (obtained from the National Collection of Type Cultures [NCTC], Colindale) was maintained in Oxoid Mueller Hinton Broth at 37° C.  Streptococcus pyogenes  strain 8198,  Staphylococcus aureus  strain 10642 (methicillin-resistant), and  E. coli  0157 strain 12900 were obtained from the NCTC, Colindale and maintained in Oxoid Mueller Hinton Broth at 37° C. 
       Fungal Growth Sensitivity Assays 
       [0150]    To determine the sensitivity of fungal strains to each of the test peptides, their impact on fungal growth was assessed as follows. Suspensions of  T. interdigitale  and  T. rubrum  conidia and hyphal fragments were prepared by adding 10 ml of fresh Nutrient Glucose Broth (NGB) (Oxoid Nutrient broth containing 2% w/v glucose) to a slope culture and agitating with a spatula. The resulting conidial/hyphal fragment suspension was filtered through 2 layers of sterile surgical gauze to remove large hyphal mats and pieces of agar. 20 μl of this suspension (absorbance at 540 nm around 0.1, corresponding to approx 10 6  propagules/ml) was inoculated into each well of sterile, 96 well microtitre plates to which a total volume 80 μl of nutrient medium (NGB) and the appropriate amount of peptide solution had previously been added. Control wells were those in which the final assay volume of 100 μl was made up with NGB medium alone, plus solvent (if applicable and at the same concentration as the peptide samples if so). Fungal growth within the plates was monitored by absorbance at 540 nm in a Microtek plate reader after 24 h, 4 day and 7 day incubations at 30° C. 
         [0000]      Candida albicans  Survival Assays 
         [0151]    To determine the sensitivity of fungal strains to each of the test peptides, their impact on  Candida  survival was assessed as follows.  C. albicans  cultures were grown for 18-24 h then stored at 4° C. prior to use. Fresh cultures grown overnight were centrifuged at 2000×g for 10 min and washed with fresh Mueller Hinton Broth, adjusting the number of viable cells to between 5×10 6  and 1×10 7 /ml. Assay buffer was prepared by adding 100 μl of NGB medium to 6.9 ml of 10 mM sodium phosphate buffer, pH 7.7. 35 μl of assay buffer with or without a range of peptide concentrations was added to a sterile polypropylene screw-capped vial and 15 μl of the  Candida albicans  inoculum described above was added. The vials were incubated at 37° C. in a water bath for 2 h, and the number of  Candida  spp. surviving was determined by serial dilution in sterile phosphate buffered saline (PBS) and plating out onto 9 cm Petri dishes containing Oxoid Sabouraud&#39;s Agar (20 ml). Counts were made after incubation of these plates at 37° C. for 18-24 h. 
       Bacterial Survival Assays 
       [0152]      Streptococcus pyogenes  strain 8198,  Staphylococcus aureus  strain 10642 (methicillin-resistant), and  E. coli  0157 strain 12900 (all obtained from the NCTC, Colindale) were grown for 18-24 h then stored at 4° C. prior to use. Fresh cultures grown overnight were centrifuged at 2000×g for 10 min and washed with fresh Mueller Hinton Broth. Sensitivity to each of the four peptides was assayed as per  C. albcans  described above. For  E. coli  and  S. aureus , the starting number of cells for the peptide sensitivity assay was 10 8 /ml and the medium used for enumeration was Nutrient Agar (Oxoid).  Str. pyogenes  grew less well than the other strains on Mueller Hinton agar and so the starting number of cells for these assays was lower than that for the other strains, at 10 6 /ml.  Str. pyogenes  survival was determined using Oxoid Tryptose Soya Agar in place of Nutrient Agar. 
       Results 
       [0153]    Table 2, below, details the peptides which correspond to the amino acid polymer codes shown in the Results and Figures. 
         [0000]                              TABLE 2               Amino acid polymer codes                                    KKK - L-Lysine trimer           RRR - L-Arginine trimer           HHH - L-Histidine trimer           WWW - L-Tryptophan trimer           pK3-14 - Poly-L-lysine-HBr 500-2,000Da (3-14aa)           pK7-27 - Poly-L-lysine-HBr 1,000-4,000Da (7-27aa)           pK100-200 - Poly-L-lysine-HCl 15,000-30,000Da (100-200aa)           pKd27-100 - Poly-D-lysine-HBr 4,000-15,000Da (27-100aa)           pR28-86 - Poly-L-arginine-HCl 5,000-15,000 (28-86aa)                        
Inhibition of  Trichophtvon  spp. Growth by Peptides 1-4
 
         [0154]    Two clinically relevant dermal fungal pathogens,  Trichopyton rubrum  and  Trichopyton interdigitale , were cultured, as described previously in the materials and methods section, in growth medium alone (control cultures) or in growth medium containing 50 μg/ml of peptide 1, 2, 3 or 4 (SEQ ID NO: 7-10, respectively; shown in  FIG. 1 ). Growth of  T. interdigitale  and  T. rubrum  was assessed by measuring the optical density (absorbance at 540 nm) after 4 and 7 days in culture. Compared to control, un-treated samples, each peptide tested significantly inhibited  T. interdigitale  ( FIG. 2 ) and  T. rubrum  ( FIG. 3 ) growth at day 4 and 7. Control cultures of each test strain continued to grow, as indicated by increases in OD readings, between days 4 and 7. 
         [0000]    Inhibition of  Candida  spp. Growth and Survival by Peptides 1-4 
         [0155]    The yeast  Candida albicans  was cultured, as described previously in the materials and methods section, in growth medium alone (control cultures) or in growth medium containing 50 μg/ml or 100 μg/ml and 300 μg/ml or 500 μg/ml of peptide 1, 2, 3 or 4. Growth of  C. albicans  was assessed by measuring optical density (absorbance at 540 nm) after 24 h ( FIG. 4   a ) and 48 h ( FIG. 4   b ) in culture. Compared to control, un-treated samples, each peptide tested significantly inhibited  C. albicans  growth in both a time and dose-dependent fashion. Dose-dependency of growth inhibition was further confirmed in experiments in which  C. albicans  growth was assessed optically after 24 h in culture under control (growth medium alone) conditions or in the presence of a range of concentrations of peptide 1, from 50 μg/ml to 500 μg/ml ( FIG. 5 ). In a separate experiment,  C. albicans  survival was assessed after 18-24 h in cultures grown in medium alone (controls) or those including a range of concentrations of peptide 4 spanning 1 μg/ml to 1000 μg/ml ( FIG. 6 ). Survival of the  C. albicans  organisms, as assessed by viability counts after 24 h in culture, decreased in a dose-dependent manner ( FIG. 6 ). 
       Inhibition of Bacterial Survival by Peptide 4 
       [0156]    Three clinically relevant bacterial pathogens,  E. coli  0157, methicillin-resistant  Staphylococcus aureus  (MRSA) and  Streptococcus pyogenes  were exposed, as described previously in the materials and methods section, to a range of concentrations of peptide 4. After a period of 3 h, samples of each bacterial culture were transferred to appropriate solid phase growth media plates and the numbers of viable colonies in control (growth medium only) and treated (growth medium containing peptide 4) samples assessed after 18-24 h. After 3 h of exposure, Peptide 4 significantly inhibited survival of each bacterial strain ( FIG. 7 ) compared to control, untreated cultures, in a dose dependent manner. 
       Acetic Acid Enhances Antifungal Activity of Peptide 4 
       [0157]    As both control (non peptide) and test (containing peptide 1, 2, 3 or 4) media in experiments shown in  FIGS. 2 and 3  contained 0.5% acetic acid as a peptide solvent (detailed in materials and methods section), a separate experiment was set up to ascertain whether the acetic acid itself might play a role in peptide activity and/or fungal survival. To this end,  T. rubrum  growth experiments were established as per methods and materials section, with growth medium only, growth medium containing only 0.01% acetic acid, growth medium containing 1 mg/ml peptide 4 and growth medium containing 1 mg/ml peptide 4 plus 0.01% acetic acid. Growth of the fungus was determined by OD as described previously after 3 days in culture. As expected, peptide 4 inhibited  T. rubrum  growth. 0.01% acetic acid alone had no significant effect on  T. rubrum  growth ( FIG. 8 ), but when included in the medium with peptide 4, the presence of 0.01% acetic acid significantly inhibited  T. rubrum  growth more than 1 mg/ml of peptide 4 alone. 
         [0000]    Inhibition of  T. interdigitale  and  T. rubrum  Growth by Peptide 4 
         [0158]    The inhibitory effects of Peptide 4 on the growth of  Trychophyton  spp. was determined by fungal growth assay as per materials and methods.  T. rubrum  and  T. interdigitale  were cultured in medium alone or in medium containing 3 different concentrations of Peptide 4. No acetic acid was present in any samples. Medium only controls were used to illustrate background absorbance of the media. Growth of the fungus was determined by the OD as described previously after 96 hours of incubation at 30° C. As shown in  FIG. 9 , these assays confirmed the inhibitory effect of Peptide 4 on the growth of both species of fungi, with  T. interdigitale  consistently more susceptible to the inhibitory effects of Peptide 4 treatment than  T. rubrum . Growth of  T. interdigitale  was inhibited at Peptide concentrations of 0.55 mg/ml. 
         [0000]    Effects of Peptides 3 and 4 on  T. interdigitale  Growth 
         [0159]    The antifungal potential of Peptide 3 and Peptide 4 on  T. interdigitale  was assessed. Growth inhibition assays were performed as per materials and methods in the absence of acetic acid. As Peptides 1-3 are highly hydrophobic and therefore insoluble they had only previously been tested against  Trichophyton  spp. in acetic acid as solvent. When  T. interdigitale  cultures were grown for 7 days in the presence of Peptide 3, Peptide 4 or medium alone with no acetic acid solvent and growth measured by OD, Peptide 4 was seen to significantly inhibit fungal growth ( FIG. 10 ), whereas Peptide 3 showed no inhibitory activity ( FIG. 10 ). This increased activity of the cationic Peptide 4 over the hydrophobic Peptide 3 in the absence of 0.5% acetic acid suggested a significant contribution of the acetic acid to the activity seen for the hydrophobic peptides previously. 
         [0000]    Effect of Acetic Acid on the Growth of  T. interdigitale    
         [0160]    The inhibition of growth of  T. interdigitale  by acetic acid was assessed by establishing fungal growth experiments as per the materials and methods section.  T. interdigitale  cultures were either grown untreated or treated with 3 different concentrations of acetic acid at 30° C. for 96 hours ( FIG. 11 ). This illustrates that there is a significant effect of 0.5% acetic acid the same concentration as was used with Peptides 1-4 previously as solvent. This experiment together with the lack of activity of Peptide 3 in the absence of acetic acid suggests that Peptide 4 is the most active compound against  Trichophyton  spp. 
         [0000]    Effect of Poly-L-Lysine on  T. interdigitale  Growth 
         [0161]    As Peptide 4 is a highly cationic peptide comprising Lysine and Arginine residues, the antifungal activity of poly-L forms of these amino acids was tested against  T. interdigitale  using growth inhibition assays as detailed in materials and methods in the absence of acetic acid. Control, untreated  T. interdigitale  cultures and those containing between 1 mg/ml and 50 μg/ml of poly-L-Lysine molecules ranging from 27-100 residues and 100-200 residues in length were established. Growth of the  T. interdigitale  in each culture was assessed after 96 hours at 30° C. Both sizes of poly-L-Lysine molecules inhibited the growth of the  T. interdigitale  ( FIG. 12 ) but whereas the larger molecule inhibited growth at all concentrations tested, inhibitory activity was seen with the molecule of 27-100 amino acids in length only at higher concentrations ( FIG. 12 ). This suggests that growth inhibition effects of Lysine on  Trichophyton  spp. is both size and dose-dependent. 
         [0000]    Effects of Poly-L-Arginine and Poly-L-Lysine on the Growth of  T. rubrum    
         [0162]    The antifungal activity of poly-L-Arginine versus poly-L-Lysine was then tested against  T. rubrum . The inhibition of growth was determined as per materials and methods in the absence of acetic acid.  T. rubrum  was cultured in medium alone, in medium containing poly-L-Arginine (28-86 amino acids in length) and poly-L-Lysine (100-200 amino acids). An uninoculated medium only control was also established. Cultures were maintained and growth monitored for 96 hours at 30° C. Poly-L-Arginine and poly-L-Lysine both inhibited the growth of  T. rubrum  ( FIG. 13 ). Poly-L-Arginine was more active in its inhibitory impact against  T. rubrum  than poly-L-Lysine when tested at equivalent doses, totally inhibiting growth at 1 mg/ml ( FIG. 13 ). 
         [0000]    Inhibition of  T. interdigitale  and  T. rubrum  by Poly-L-Arginine 
         [0163]    The inhibition of growth of  Trychophyton  spp. by poly-L-Arginine was tested by setting up fungal growth experiments as per the materials and methods section.  T. rubrum  and  T. interdigitale  cultures were either grown in medium alone or in medium containing 3 different concentrations of poly-L-Arginine. No acetic acid was present in any samples. Medium controls were used to illustrate background absorbance of the media. Growth of the fungus was determined by the OD as described previously after 96 hours of incubation at 30° C. ( FIG. 14 ). Polyarginine is seen to be active against both species of fungi down to 0.55 mg/ml ( FIG. 14 ). 
         [0000]    Effect of Reduced Concentration (100 μg/ml) of Polyarginine on  T. rubrum  and  T. interdigitale    
         [0164]    The inhibition of growth of  Trychophyton  spp. by polyarginine was tested by setting up fungal growth experiments as per the materials and methods section.  T. rubrum  and  T. interdigitale  cultures were either grown untreated or treated with a single concentration of polyarginine (100 μg/ml), with no acetic acid present in any samples. Medium controls were used to illustrate background absorbance of the media. Growth of the fungus was determined by the OD as described previously after 96 hours of incubation at 30° C. ( FIG. 15 ). The reduced concentration leads to a loss of activity, this illustrates the dose effect of the polyarginine on the  Trychophyton  spp. 
         [0000]    The Effect of Peptide Trimers (3 Amino Acids) on the Growth of  T. rubrum    
         [0165]    The activity of peptide trimers of poly-L-Lysine, poly-L-Arginine, poly-L-Histidine and poly-L-Tryptophan on the growth of  T. rubrum  was tested. The inhibition of growth was set up as per the materials and methods and  T. rubrum  was either left untreated or exposed to 2 mg/ml of each of the trimers. Cultures were maintained for 96 hours at 30° C. Fungal growth was measured by OD and the results displayed as a percentage of the growth in the untreated culture ( FIG. 16 ). Poly-L-Arginine was the most active peptide against  T. rubrum  with only a 3 amino acid polypeptide required to elicit a significant reduction in growth of  T. rubrum.    
         [0000]    Effect of Peptide 4 (1.2 mg/ml) and Nacl on Growth of  T. interdigitale    
         [0166]    The impact of various salt concentrations on the antifungal activity of Peptide 4 towards  T. interdigitale  was investigated.  T. interdigitale  growth inhibition assays were set up as per the materials and methods in the absence of acetic acid. Cultures were left untreated or exposed to Peptide 4 plus a range of NaCl concentrations from 100 mM to 500 mM.  T. interdigitale  cultures were maintained for 96 h at 30° C. and growth assessed by OD as described previously ( FIG. 17 ). The antifungal activity of Peptide 4 was not affected by to salt concentrations close to or in excess of those found under physiological conditions ( FIG. 17 ). The antimicrobial activities of endogenous β-defensins are well-reported as being inhibited by even low salt concentrations. 
         [0000]    Effect of Peptide 4 Against  Candida albicans  at High Salt Concentrations 
         [0167]    Survival of  C. albicans  was assessed as detailed in methods and materials following a 2 h incubation at 37° C. with a range of concentrations of Peptide 4. Two concentrations of NaCl were introduced into the growth medium to ascertain the impact of physiological and very high salt conditions (known to inhibit endogenous (3-defensin peptide activity). Significant killing activity of Peptide 4 was observed at even very high salt concentrations ( FIG. 18 ). As the concentration of Peptide 4 is increased it can be seen that the impact of the higher salt concentration is reduced ( FIG. 18 ). Therefore, the fungicidal activity of Peptide 4 is not inhibited by salts. 
         [0000]    Activity of Poly-L Lysine, Poly-D-Lysine and Poly-D-Arginine Against  Candida albicans    
         [0168]    The antifungal activity of poly-L Arginine versus Lysine and poly-L versus poly-D Lysine was assessed in order to determine, which if any of these peptide variants demonstrated enhanced activity against  Candida albicans. Candida  spp. was incubated as described in the materials and methods section for 2 hours at 37° C. in the presence of 100 μg/ml, 1 mg/ml and 10 mg/ml poly-D-lysine, poly-L-lysine and poly-L-Arginine. Survival was assessed as detailed previously and demonstrates increased antifungal activity of poly-L-Arginine over the poly-L-lysine ( FIG. 19 ). It also demonstrates that the poly-D-lysine has very similar antifungal activity to the poly-L-lysine.