Patent Publication Number: US-5834430-A

Title: Potentiation of antibiotics

Description:
FIELD OF THE INVENTION 
     The present invention is concerned with providing a method of potentiating antibiotics and new compositions which comprise an antibiotic and a potentiating agent which comprises a peptide which binds to lipopolysaccharide (LPS). 
     BACKGROUND OF THE INVENTION 
     Antibiotics are widely used in medicine for the treatment of infections caused by susceptible microbiological organisms. Many of these drugs have toxic side effects and/or require increased doses for the treatment of certain infections. The applicants have discovered that many different types of antibiotics, which are chemically dissimilar, may be potentiated if an effective amount of a peptide which binds to LPS is coadministered with an antibiotic to treat an infection which is caused by a susceptible organism. Certain of these peptides are disclosed in U.S. Pat. No. 5,371,186, which is incorporated by reference. 
     SUMMARY OF THE INVENTION 
     The applicant has discovered that antibiotics are potentiated when they are coadministered with peptides which contain the basic amino acid units (homopolymer units) as well as the basic and hydrophobic amino acids (heteropolymer units) according to the formulae: (A) n , (AB) n , and (ABC) n  where A is any cationic amino acid (at a pH of about 7.0); B and C are any hydrophobic amino acid, both (the aliphatic cationic amino acid and the hydrophobic amino acid) that are characterized by solvent parameter values equal to or greater than +1.5kcal/mol and -1.5 kcal/mol respectively, may be coadministered with an antibiotic to potentiate the antibiotic effect of the antibiotic. The potentiation of the antimicrobial effect of an antibiotic allows the dose of the antibiotic to be reduced while achieving the same in vivo or in vitro effect. 
     Accordingly, it is a primary object of the invention to provide a means of potentiating an antibiotic. 
     It is also an object of the invention to provide novel compositions for the treatment or prophylaxis of microbial infections. 
     It is also an object of the invention to provide novel methods for the treatment or prophylaxis of microbial infections which use reduced doses of antibiotic drugs. 
     It is also an object of this invention to provide novel compositions and methods for the treatment of microbial infections. 
     These and other objects of the invention will become apparent from the appended specification. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 graphically shows the effect of the peptide identified herein by Sequence ID No.:31 on the potentiation of rifampin and a combination of novobiocin and erythromycin on Escherichia coli IH3080 (clinical isolate). 
     FIG. 2 graphically shows the effect of the peptide identified herein by Sequence ID No.:31 on the potentiation of rifampin and novobiocin on Enterobacter cloacae 12645 (clinical isolate). 
     FIG. 3 graphically shows the potentiation of antibiotic activity of the peptide identified herein by Sequence ID NO.: 31 on the potentiation of rifampin and a combination of novobiocin and erythromycin on Salmonella typhimurium SH5014. 
     FIG. 4 graphically shows the potentiation of antibiotic activity of the peptide identified herein by Sequence ID NO.: 31 on the potentiation of rifampin on Pseudomaonas aeruginosa PA01 (clinical isolate). 
     FIG. 5 graphically shows the potentiation of antibiotic activity of the peptide identified herein by Sequence ID NO.: 31 on the potentiation of novobiocin and rifampin on Klebsiella pneumoniae 12854 (clinical isolate). 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The peptides of the invention have not exhibited any growth inhibitory activity against bacteria when they have been used in the absence of an antibiotic substance. The ability of the peptides to potentiate the activity of antibiotics was therefore unexpected. The inventors do not wish to be bound by any theory by which the invention may be explained but it is believed that the peptides of the invention interact with the membrane of pathogenic bacteria, particularly the outer membrane of gram-negative bacteria which contains LPS. The interaction of the peptide and the LPS of the bacterial outer membrane is believed to increase the permeability of the membrane to antibiotics, particularly hydrophobic/lipophilic antibiotics. 
     The term antibiotic is used according to Tabers Cyclopedic Medical Dictionary, 15th Ed. to describe antimicrobial substances which have the ability to inhibit the growth of or to destroy microorganisms. These substances are active in dilute solutions and may be produced in whole or in part by a microorganism or by a synthetic or semi-synthetic method. 
     Antibiotics which are useful in the present invention include penicillin derivatives such as penicillin G, penicillin V, penicillin G benzathine, ampicillin, amoxacillin, nafcillin, carbenicillin, dicloxacillin, bacampicillin, piperacillin, ticaricillin, mezlocillin and the like; cephalosporins such as cefazolin, cefadroxil, cephalexin, cefaclor, cefoxitin, cefonicid, ceftizoxime, cefprozil, ceftazidine, cefixime, cefpodoxime proxitel and the like; aminoglycosides such as amikacin, gentamicin, tobramycin, netilmicin, streptomycin and the like; macrolides such as erythromycin and the like; monobactams such as aztreonam and the like; rifamycin and derivatives such as rifampin, rifamide, rifaximin and the like; chloramphenicol; clindamycin; lincomycin; imipenem; vancomycin; tetracyclines such as chlortetracycline, tetracycline, minocycline, doxycycline and the like; fusidic acid; novobiocin and the like; fosfomycin, fusidate sodium, neomycin, bacitracin, polymyxin, capreomycin, colistimethate, colistin and gramicidin. 
     In addition, a peptide may be used with one antibiotic or it may be used in combination with more than one antibiotic and/or in combination with other antibacterial agents. Suitable combinations include: 
     rifampin+erythromycin 
     erythromycin+sulfonamide such as sulfisoxazole 
     penicillin+streptomycin 
     rifampin+beta lattamin 
     rifampin+fluoroquinolones 
     rifampin+vancomycin 
     rifampin+tetracyclines 
     rifampin+trimetoprim 
     novobiocin+fluoroquinolones 
     trimetoprim+sulfonamides 
     rifampin+fusidic acid 
     rifampin+isoniazid 
     rifampin+fosfomycin 
     rifampin+clofazmin+dapsone 
     rifampin+aminoside 
     vancomycin+fusidic acid 
     Many of the antimicrobial drugs are described in Remingtons Pharmaceutical Sciences, 15th Ed., Chapter 64, which is incorporated by reference. 
     The peptides which are useful for potentiating the activity of antibiotics are linear or cyclic peptides having units of the formula: 
     (a) (A) n  wherein A is Lysine or Arginine and n is an integer with a minimum value of 7; 
     (b) (AB) m  wherein A is Lysine or Arginine and B is a hydrophobic amino acid selected from the group consisting of Valine, Leucine, Isoleucine, Tyrosine, Phenylalanine and Tryptophan; m is an integer with a minimum value of 3; and (c) (ABC) p  wherein A is a cationic amino acid which is Lysine or Arginine; B and C are hydrophobic amino acids which may be the same or different and are selected from the group consisting of Valine, Leucine, Isoleucine, Tyrosine, Phenylalanine and Tryptophan; p is an integer with a minimum value of 2. The peptides of the invention may be terminated independently with a hydrogen atom or any of the naturally occurring amino acids, a fatty acid residue or a carbohydrate residue. In addition the retroinverted peptides of the peptides described herein may also be employed. 
     The preferred peptides for use in the invention will also have a ratio of aliphatic cationic amino acids to hydrophobic amino acids (R c/h ) of at least 0.5 and within the range of about 0.5 to 10.0 which is computed by using the solvent parameter values only for those amino acids which are present in the peptides which have a solvent parameter value equal to or greater than +1.5kcal/mol (lysine and arginine) and -1.5kcal/mol (valine, isoleucine, leucine, tryrosine, phenylalanine and tryptophane) as measured according to Levitt, J. Mol. Biol. 104,59 (1976), which is incorporated by reference. 
     The minimal effective peptide sequence for use in potentiating an antibiotic comprises six to seven amino acid residues containing a minimum of three aliphatic cationic amino acids, with a ratio of aliphatic cationic amino acids to hydrophobic amino acids of equal to or greater than 0.5 (R c/h  wherein c is the number of cationic amino acids in the peptide and h is the number of hydrophobic amino acids in the peptide). This ratio is believed to be the minimum although sequences of ten amino acids with a ratio (R c/h ) equal to or greater than 1.0 are optimal for expression of biological activity. 
     The peptide units which are represented by formula (a), (b) and (c) represent discrete peptides which will potentiate antibiotics have specific formulas which are identical with the units of formula (a), (b) and (c) as well as peptides which will bind endotoxin in the LAL inhibition test and which include as a part of their structure units of formula (a), (b) and (c), in addition to other amino acids, are included within the peptides which comprise the invention. 
     The peptides should not exhibit hemolytic activity when equal volumes of a solution of the peptide in isotonic saline, at a minimum peptide concentration of 0.1 mg/ml and a solution of 10%w/w fresh human erythrocytes in isotonic saline are incubated at 37° C. for 30 minutes and no rupture of the erythrocytes and release of hemoglobin is detected visually or by use of a spectrophotometer (540 nm). 
     The minimum values for n, m and p have been determined experimentally on the basis of the observation that when the peptide is linear, it will have at least 7 amino acid units and when said peptide is cyclic or a polymer having several cycles, i.e. 2 to 6 cycles, it will have a ring structure that has a minimum of 6 amino acid units and preferably a maximum of 7 amino acid units; said peptides having a ratio of aliphatic cationic amino acids to hydrophobic amino acids which is equal to or greater than 0.5. 
     When the peptides are of the formula (A) n , (AB) m  or (ABC) p , i.e. when these formulas do not represent units of a larger peptides, n will be from 7 to 500 and preferably from 7 to 10; m will be from 3 to 200 and preferably from 4 to 20 and p will be from 2 to 100 and preferably from 4 to 20. 
     Examples of the peptides are listed below. Those peptides which are not novel are marked by an asterisk: ##STR1## 
     The peptides for use in the present invention may be synthesized by classical methods of peptide chemistry using manual or automated techniques as well as by DNA recombinant technology. The synthetic procedure comprises solid phase synthesis by Fmoc chemistry, cleavage (TFA 95%+Et-(SH) 2  5%), followed by vacuum evaporation. Thereafter, the product is dissolved in 10% acetic acid, extracted with ether, concentrated at 0.1 mg/ml at pH of 6.0-7.5. Stirring under filtered air followed for 1 to 6 hours in case of the Cysteine-containing peptides and finally desalting by reverse phase chromatography is carried out. 
     A particular automated method of preparing peptides for use in the present invention is based on the use of an automatic synthesizer (Milligen Mod.9050 (MILLIPORE, Burlington, Mass.) on a solid phase support of polyamide/Kieselguhr resin (2.0 g). The amino acids used in the synthesis of the peptide analogs are Fmoc-aa-Opfp derivatives (9-Fluorenylmethylcarbonyl-aa-O-pentafluorophenyl ester) of each amino acid(aa) involved in the considered sequences using 0.8 mol of each amino acid to sequentially form the peptide. 
     Each cycle of synthesis may be performed at room temperature (20° C.) and involves the following steps of reaction: 
     Step 1--Deprotection 
     The first aa Fmoc-protected at the amino group, was treated with a 20% solution of piperidine for 7 minutes in order to remove the Fmoc alpha-protecting group. Washing with dimethylformamide followed for 12 minutes to remove all traces of piperidine. Deprotection and washing were run continuously through the column containing the resin by means of a pump at a flow of 5 ml/min. 
     Step 2--Activation of the Fmoc-aa-Opfp derivative 
     The amino and carboxy-protected amino acid due, according to the desired sequence, was activated after its dissolution in 5 ml of dimethylformamide, by a catalytic amount of hydroxybenzotriazol (0.5 ml of a 5% w/v solution in dimethylformamide). 
     Step 3--Acylation 
     The activated and protected Fmoc-aa-Opfp derivative was then recycled for 30 minutes through the column by the pump at 5 ml/min in order to obtain coup ling of the introduced aa at the alpha-amino group (previously deprotected as reported in Step 1) of the amino acid preceding the new one in the desired sequence. 
     Step 4--Washing 
     Washing of the matrix in the column followed by dimethylformamide for 2 minutes at 5 ml/min before a new cycle began. 
     At the completion of the synthesis, the peptide on the resin support was cleaved by 95% Trifluoroacetic acid (TFA) with 5% Ethane dithiol as a scavenger, if Cysteine residues were present in the aa sequence, at room temperature for 2 hours. After separation of the cleaved peptide from the resin by filtration, the solution was concentrated by vacuum evaporation to dryness. The collected solid residue was then solubilized in 10% acetic acid at a concentration of 10-20 mg/ml and several extractions by diethyl ether followed (six to eight extractions with half the volume of the peptide solution) in order to remove the scavenger Ethane dithiol. The peptide solution was then neutralized by 0.1N ammonium hydroxide and adjusted to the concentration of roughly 0.1 mg/ml. The solution was then stirred under air for 1 to 6 hours in order to obtain the selective oxidation of the two sulfhydryl groups belonging to the Cys residues of the sequence. In this way, only monomeric oxidized peptides were obtained with no traces of polymeric material. The solution of oxidized peptide was then desalted by reverse-phase chromatography on SEP-PAK C-18 cartridges (MILLIPORE) and finally freeze dried. The products were analyzed by high-performance liquid chromatography (HPLC) analysis as well as by chemical analysis of the synthetic structures. 
     Fast atom bombardment may be used to confirm the calculated mass of the peptides. 
     The peptides described herein which exhibit the absence or a low level of hemolysis may be used in the treatment of infections in mammals including humans at doses of about 0.1 mg-2.0 mg/kg of body weight or may be used at a level of about 0.2 mg to about 1.0 mg/kg of body weight and the amount may be administered in divided doses on daily basis prior to, simultaneously with or after the administration of an antibiotic. Generally the doses of the antibiotic will be reduced by from about 90% to about 10% of the standard therapeutic dose of a given antibiotic as shown in standard compendia such as the 1994 Physicians Desk Reference, which is incorporated by reference. The combination of the peptide and the antibiotic may be administered prophylactically to patients who may be exposed to or have been exposed to organisms which may cause infection. The particular dose of a particular peptide with a particular antibiotic may be varied within or without the range that is specified herein depending on the particular application or severity of the infection and the condition of the host. Those who are skilled in the art may ascertain the proper dose using standard procedures. A convenient dose of a combined formulation of the peptide and the antibiotic may be 0.1-1.0 mg/Kg of body weight of peptide with 0.25-40 mg/Kg of body weight of antibiotic administered daily in single or multiple doses in order to achieve and maintain therapeutic plasma concentrations. 
     The peptides may be administered intravenously and parenterally using well known pharmaceutical carriers or inert diluents and the antibiotics may be administered intravenously, parenterally or orally depending on the particular antibiotic. Aqueous, physiologically compatible diluents are preferred. A composition containing both the peptide and the antibiotic may be placed in the same sterile container for dilution with a suitable diluent such as sterile isotonic saline or sterile water for injection prior to administration. If the peptide and the antibiotic are not compatible, they may be placed in containers that provide a means for separation of the components until just prior to use or they may be placed in separate containers. The invention also includes topical preparations containing the peptide and antibiotic in the form of ophthalmic ointments or drops; otological preparations such as viscous liquids e.g. propylene glycol based sterile solutions or dispersions; and topical creams and ointments for the treatment and/or prevention of skin infections. Suitable vehicles and the techniques for preparing suitable vehicles are set forth in Remingtons Pharmaceutical Sciences, 17th Ed., Mack Pub. Co., Easton, Pa. 18042, Chapters 84, 87 and 88, which is incorporated by reference. Generally the concentration of the peptide and the antibiotic in these preparations will be sufficient to exert an antimicrobial effect. These amounts will vary depending on the particular drugs which are selected and may be determined by routine experimentation. Generally the peptides may be used at a concentration of 0.1-5 wt % and the antibiotics may be used at from 90% to 10% of the usual therapeutic amount. 
     When other antibacterial agents are used in combination with an antibiotic and the peptide composition, the total amount of the antibacterial may also be reduced from 10 to 90% while still obtaining an enhanced therapeutic response with reduced toxicity. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Example 1 
     The growth inhibition of the combination of a peptide and an antibiotic was demonstrated in vitro using microdilution plates, the checkerboard technique and a bacterial inoculum size of 10 4  bacterial cells/ml. The general assay medium was L broth (pH7.2) which contained 10 g of tryptone (Difco Laboratories, Detroit, Mich.), 5 g of yeast extract (Oxoid Ltd., Hampshire, UK) and 5 g of sodium chloride per liter. After an incubation time of 18 hours at 37° C., the growth of each microtiter well is measured with a Titerteck Multiscan spectrophotometer at 405 nm. Before reading, the spectrophotometer was blanked with corresponding uninoculated drug-containing media. The minimum inhibitory concentration (MIC) of an antibiotic was defined as the lowest concentration of the antibiotic expressed in mg/l which reduced the growth of the target bacteria by ≧90% (MIC 90 ). The results of the MIC tests show that the combination of an antibiotic and a peptide provides synergistic growth inhibition activity. These results are summarized in Table I and are shown specifically for a representative peptide in FIG. 1 and FIG. 2. 
     
                       TABLE I                                                     
______________________________________                                    
      Concentration                                                       
                 E. coli IH3080                                           
                               E. coli IH3080                             
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
None  0          10            300                                        
30    1          10            300                                        
      10         3             300                                        
      100        0.1            10                                        
31    1          3             300                                        
      10         1             100                                        
      100        0.1            10                                        
35    1          10            300                                        
      10         3             100                                        
      100        1             100                                        
40    1          1             100                                        
      10         0.03           1                                         
41    1          1             100                                        
      10         0.03           1                                         
      30         0.01           1                                         
______________________________________                                    
      Concentration                                                       
                 E. coli IH3080                                           
                               E. coli IH3080                             
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq, ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
None  0          30             30                                        
30    1          30             30                                        
      10         10             30                                        
      100        1              1                                         
31    1          30             30                                        
      10         3              10                                        
      100        1              1                                         
35    1          30             30                                        
      10         30             30                                        
      100        3              30                                        
40    1          1              30                                        
      10         1              3                                         
      30         1              1                                         
41    1          10             10                                        
      10         1              1                                         
______________________________________                                    
      Concentration                                                       
                 E. coli IH3080                                           
                               E. coli IH3080                             
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
42    1          10            300                                        
      10         3             300                                        
43    1          10            300                                        
      10         1             100                                        
      30         0.1            10                                        
26    1          10            300                                        
      10         1             300                                        
      100        0.3            30                                        
28    1          1             300                                        
      10         0.3           100                                        
      100        0.01           1                                         
______________________________________                                    
      Concentration                                                       
                 E. coli IH3080                                           
                               E. coli IH3080                             
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
42    1          10            100                                        
      10         10             30                                        
43    1          30            100                                        
      10         10             30                                        
      30         1              1                                         
26    1          30             30                                        
      10         10             30                                        
      100        3              10                                        
28    1          10             30                                        
      10         3              10                                        
      100        1              1                                         
______________________________________                                    
      Concentration                                                       
                 S. typhi SH5014                                          
                               S. typhi SH5014                            
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
None  0          10            &gt;300                                       
30    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        0.1            30                                        
31    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        0.03           3                                         
35    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        3             300                                        
40    1          3             100                                        
      10         0.01           1                                         
41    1          3             100                                        
      3          0.01           1                                         
______________________________________                                    
      Concentration                                                       
                 S. typhi SH5014                                          
                               S. typhi SH5014                            
Peptide                                                                   
      of Peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/ml)    MIC Novobiocin                                           
                               MIC Erythromycin.                          
______________________________________                                    
None  0          30            100                                        
30    1          30            100                                        
      10         30            100                                        
      100        1              10                                        
31    1          10            100                                        
      10         10            100                                        
      100        1              3                                         
35    1          30            100                                        
      10         10            100                                        
      100        10            100                                        
40    1          10            100                                        
      10         1              1                                         
41    1          10            100                                        
      3          1              1                                         
______________________________________                                    
      Concentration                                                       
                 S. typhi SH5014                                          
                               S. typhi SH5014                            
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
42    1          10            &gt;300                                       
      10         10            300                                        
43    1          10            &gt;300                                       
      10         3             300                                        
      30         0.1            1                                         
26    1          10            &gt;300                                       
      10         3             100                                        
      100        0.3            30                                        
28    1          10            300                                        
      10         1             300                                        
      30         0.1           100                                        
______________________________________                                    
      Concentration                                                       
                 S. typhi. SH5014                                         
                               S. typhi. SH5014                           
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
42    1          30            100                                        
      10         10            100                                        
43    1          30            100                                        
      10         10            100                                        
      30         1              1                                         
26    1          30            100                                        
      10         10            100                                        
      100        3              30                                        
28    1          10            100                                        
      10         3             100                                        
      30         1              10                                        
______________________________________                                    
      Concentration                                                       
                 Ps. aeroginosa. PAO1                                     
                               Ps. aeroginosa. PAO1                       
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
None  0          &gt;10           &gt;300                                       
30    1          &gt;10           &gt;300                                       
      10         &gt;10           &gt;300                                       
      100        10            &gt;300                                       
31    1          &gt;10           &gt;300                                       
      10         10            &gt;300                                       
      100        3             300                                        
______________________________________                                    
      Concentration                                                       
                 Ps. aeroginosa PAO1                                      
                               Ps. aeroginosa. PAO1                       
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
None  0          &gt;30           100                                        
30    1          &gt;30           100                                        
      10         &gt;30           100                                        
      100        &gt;30           100                                        
31    1          &gt;30           100                                        
      10         &gt;30           100                                        
      100        &gt;30           100                                        
______________________________________                                    
      Concentration                                                       
                 Kl. pneumoniae 12854                                     
                               Kl. pneumoniae 12854                       
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
None  0          10            &gt;300                                       
30    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        1             100                                        
31    1          10            &gt;300                                       
      10         10            300                                        
      100        1              30                                        
35    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        10            300                                        
40    1          10            100                                        
      10         0.1            10                                        
      100        0.01           1                                         
41    1          3             300                                        
      10         0.03           3                                         
      30         0.01           1                                         
______________________________________                                    
      Concentration                                                       
                 Kl. pneumoniae 12854                                     
                               Kl. pneumoniae 12854                       
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
None  0          30            &gt;100                                       
      1          30            &gt;100                                       
      10         30            &gt;100                                       
      100        10             30                                        
31    1          30            &gt;100                                       
      10         30            &gt;100                                       
      100        3              30                                        
35    1          30            &gt;100                                       
      10         30            &gt;100                                       
      100        10            &gt;100                                       
40    1          30            &gt;100                                       
      10         3              3                                         
      100        1              1                                         
41    1          10            &gt;100                                       
      10         1              3                                         
      30         1              1                                         
______________________________________                                    
      Concentration                                                       
                 Kl. pneumoniae 12854                                     
                               Kl. pneumoniae 12854                       
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
42    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        1             100                                        
43    1          10            &gt;300                                       
      10         10            300                                        
      100        0.3            30                                        
26    1          10            &gt;300                                       
      10         10            300                                        
      100        3             100                                        
28    1          10            &gt;300                                       
      10         10            300                                        
      100        1              30                                        
______________________________________                                    
      Concentration                                                       
                 Kl. pneumoniae 12584                                     
                               Kl. pneumoniae 12584                       
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythromycin.                          
______________________________________                                    
42    1          30            &gt;100                                       
      10         30            &gt;100                                       
      100        1              10                                        
43    1          30            &gt;100                                       
      10         30            &gt;100                                       
      100        3              10                                        
26    1          30            &gt;100                                       
      10         30            &gt;100                                       
      100        10            100                                        
28    1          30            &gt;100                                       
      10         10            100                                        
      100        3              30                                        
______________________________________                                    
      Concentration                                                       
                 E. cloa12645  E. cloa 12645                              
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin  MIC Fusidic a.                             
______________________________________                                    
None  0          10            &gt;300                                       
30    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        0.3            30                                        
31    1          10            &gt;300                                       
      10         10            300                                        
      100        1              30                                        
35    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        3             300                                        
40    1          3             100                                        
      10         0.1            3                                         
      100        0.01           1                                         
41    1          3             100                                        
      10         0.03           1                                         
      30         0.01           1                                         
______________________________________                                    
      Concentration                                                       
                 E. cloa 12645 E. cloa. 12645                             
Peptide                                                                   
      of Peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
None  0          &gt;30           &gt;100                                       
30    1          &gt;30           &gt;100                                       
      10         &gt;30           &gt;100                                       
      100        10             30                                        
31    1          &gt;30           &gt;100                                       
      10         &gt;30           &gt;100                                       
      100        10            100                                        
35    1          &gt;30           &gt;100                                       
      10         &gt;30           &gt;100                                       
      100        30            &gt;100                                       
40    1          10            100                                        
      10         1              1                                         
      100        1              1                                         
41    1          30            &gt;100                                       
      10         1              1                                         
      30         1              1                                         
______________________________________                                    
      Concentration                                                       
                 E. cloa 12645 E. cloa 12645                              
Peptide                                                                   
      of peptide Experiment I  Experiment II                              
Seq. ID                                                                   
      (mg/1)     MIC Rifampin. MIC Fusidic a.                             
______________________________________                                    
42    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        0.01           30                                        
43    1          10            &gt;300                                       
      10         3             &gt;300                                       
      100        0.3            30                                        
26    1          10            &gt;300                                       
      10         10            &gt;300                                       
      100        1             100                                        
28    1          10            &gt;300                                       
      10         3             300                                        
      100        1             100                                        
______________________________________                                    
      Concentration                                                       
                 E. cloa. 12645                                           
                               E. cloa. 12645                             
Peptide                                                                   
      of peptide Experiment III                                           
                               Experiment IV                              
Seq. ID                                                                   
      (mg/1)     MIC Novobiocin                                           
                               MIC Erythrom.                              
______________________________________                                    
42    1          &gt;30           &gt;100                                       
      10         &gt;30           &gt;100                                       
      100        3              10                                        
43    1          &gt;30           &gt;100                                       
      10         &gt;30           100                                        
      100        10             10                                        
26    1          &gt;30           &gt;100                                       
      10         30            &gt;100                                       
      100        10            100                                        
28    1          &gt;30           &gt;100                                       
      10         30            100                                        
      100        10            100                                        
______________________________________                                    
 
    
     The data in Table II shows that the peptides when used alone have no significant antibacterial activity. These data were obtained using the general procedure set forth above: 
     
                       TABLE II                                                    
______________________________________                                    
            Peptide SEQ ID NO:                                            
Bacterial strain                                                          
              30      31     35    40    41                               
______________________________________                                    
E. coli IH3080                                                            
              &gt;100    &gt;100   &gt;100  100   30                               
S. Typhimurium SH5014                                                     
              &gt;100    &gt;100   &gt;100  30    30                               
Klebs pneum. 12854                                                        
              &gt;100    &gt;100   &gt;100  &gt;100  100                              
Enterob. cloacae 12654                                                    
              &gt;100    &gt;100   &gt;100  &gt;100  100                              
Pseud. aeroginosa PAO1                                                    
              &gt;100    &gt;100   &gt;100  30    30                               
E. coli SM 101                                                            
              &gt;100    &gt;100   &gt;100  30    10                               
Micrococcus luteus ML36                                                   
                100     100  &gt;100  10    30                               
______________________________________                                    
               Peptide SEQ ID NO:                                         
               42        43      26    28                                 
______________________________________                                    
E. coli IH3080 30         100    &gt;100  &gt;100                               
S. Typhimurium SH5014                                                     
               30         100    &gt;100    100                              
Klebs pneum. 12854                                                        
               &gt;100      &gt;100    &gt;100  &gt;100                               
Enterob. cloacae 12654                                                    
               &gt;100      &gt;100    &gt;100  &gt;100                               
Pseud. aeroginosa PAO1                                                    
               &gt;100      &gt;100    &gt;100  &gt;100                               
E. coli SM 101 30           30   &gt;100    100                              
Micrococcus luteus ML36                                                   
               10           30   &gt;100     30                              
______________________________________                                    
 
    
     Example 
     A human patient suffering from an infection caused by K. pneumoniae may be treated with a combination of Rifampin (0.5 mg/Kg of body weight/IV every 8 hours in normal saline) and Lys-Thr-Lys-Cys-Lys-Phe-Leu-Lys-Lys-Cys s-----------------------s (SEQ ID No.:31) (1 mg/Kg of body weight/IV every 8 hours in normal saline). The dose of Rifampin is 10 to 20% by weight of the usual clinical dose of Rifampin which is administered as the sole therapeutic agent. This reduces the possibility of any toxic side effects of Rifampin without reduction of the clinical efficacy of Rifampin. 
     
         __________________________________________________________________________
SEQUENCE LISTING                                                          
(1) GENERAL INFORMATION:                                                  
(iii) NUMBER OF SEQUENCES: 45                                             
(2) INFORMATION FOR SEQ ID NO:1:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                   
LysLysLysLysLysLysLysLysLysLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:2:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 30 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                   
LysLysLysLysLysLysLysLysLysLys                                            
1510                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
1520                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
2530                                                                      
(2) INFORMATION FOR SEQ ID NO:3:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 434 amino acids                                               
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                   
LysLysLysLysLysLysLysLysLysLys                                            
1510                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
1520                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
2530                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
3540                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
4550                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
5560                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
6570                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
7580                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
8590                                                                      
LysLysLysLysLysLysLysLysLysLys                                            
95100                                                                     
LysLysLysLysLysLysLysLysLysLys                                            
105110                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
115120                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
125130                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
135140                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
145150                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
155160                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
165170                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
175180                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
185190                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
195200                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
205210                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
215220                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
225230                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
235240                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
245250                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
255260                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
265270                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
275280                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
285290                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
295300                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
305310                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
315320                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
325330                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
335340                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
345350                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
355360                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
365370                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
375380                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
385390                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
395400                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
405410                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
415420                                                                    
LysLysLysLysLysLysLysLysLysLys                                            
425430                                                                    
LysLysLysLys                                                              
(2) INFORMATION FOR SEQ ID NO:4:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                   
LysAspLysAspLysAspLysAspLysAsp                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:5:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                   
LysPheLysPheLysPheLysPheLysPhe                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:6:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                   
LysPheLeuLysLysThrLeu                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:7:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                   
LysPheLeuLysPheLeuLys                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:8:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                   
LysPheLeuLysPheLeuLysPheLeuLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:9:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                   
ArgTyrValArgTyrValArgTyrVal                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:10:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                  
LysPhePheLysPhePheLysPhePheLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:11:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                  
LysLeuLeuLysLeuLeuLysLeuLeu                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:12:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                  
LysLysLysLysLysLysPheLysPheLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:13:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 11 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                  
CysLysCysLysCysLysCysLysCysLysCys                                         
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:14:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                  
CysLysPheLysLysCys                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:15:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                  
LysPheLysCysLysPheLysPheLysCys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:16:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                  
LysLeuLysCysLysLeuLysLeuLysCys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:17:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                  
ArgThrArgCysArgPheLysArgArgCys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:18:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                  
LysCysLysPheLysLysPheLysCysLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:19:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                  
CysLysLysLysLysPhePhePhePheCys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:20:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 12 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                  
CysLysPheLeuLysPheLeuLysPheLeuLysCys                                      
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:21:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                  
ValLysAlaLeuArgValArgArgLeu                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:22:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 11 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                  
LysSerLeuSerLeuLysArgLeuThrTyrArg                                         
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:23:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                  
LysValArgLysSerPhePheLysVal                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:24:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                  
PheLeuLysProGlyLysValLysVal                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:25:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 8 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                  
LysGluLeuLysArgIleLysIle                                                  
15                                                                        
(2) INFORMATION FOR SEQ ID NO:26:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                  
LysTrpLysAlaGlnLysArgPheLeu                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:27:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                  
LysTrpLysAlaGlnLysArgPheLeuLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:28:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 11 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                  
LysArgLeuLysTrpLysTyrLysGlyLysPhe                                         
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:29:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 13 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                  
CysGlnSerTrpLysSerSerGluIleArgCysGlyLys                                   
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:30:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                  
CysLysPheLeuLysLysCys                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:31:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                  
LysThrLysCysLysPheLeuLysLysCys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:32:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 6 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                  
LysPheLeuLysLysThr                                                        
15                                                                        
(2) INFORMATION FOR SEQ ID NO:33:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                  
CysLysLysLeuPheLysCysLysThrLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:34:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                  
CysLysLysLeuPheLysCysLysThr                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:35:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 11 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                  
IleLysThrLysCysLysPheLeuLysLysCys                                         
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:36:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                  
IleLysThrLysLysPheLeuLysLysThr                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:37:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 11 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                  
IleLysPheLeuLysPheLeuLysPheLeuLys                                         
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:38:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 7 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                  
LysPheLeuLysPheLeuLys                                                     
15                                                                        
(2) INFORMATION FOR SEQ ID NO:39:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                  
ArgTyrValArgTyrValArgTyrVal                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:40:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 9 amino acids                                                 
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                  
LysPhePheLysPhePheLysPhePhe                                               
15                                                                        
(2) INFORMATION FOR SEQ ID NO:41:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                  
IleLysPheLeuLysPheLeuLysPheLeu                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:42:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                  
LysLysLysLysLysLysPheLeuPheLeu                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:43:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                  
CysLysPheLysPheLysPheLysPheCys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:44:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 10 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                  
LysTrpLysAlaGlnLysArgPheLeuLys                                            
1510                                                                      
(2) INFORMATION FOR SEQ ID NO:45:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 11 amino acids                                                
(B) TYPE: amino acid                                                      
(C) TOPOLOGY: circular                                                    
(ii) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                  
LysArgLeuLysTrpLysTyrLysGlyLysPhe                                         
1510                                                                      
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