bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology
Authors: Ruscoe J. E. , Tingle M. D. , O’Neill P. M. , Ward S. A. , Park B. K. 
Published: October 2018

ABSTRACT
The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5′ position of amodiaquine reduced or eliminated bioactivation, as determined by glutathione conjugate formation in vivo. This can be seen in two series of C-5′-substituted compounds: the bis-Mannich antimalarial agents, including cycloquine and pyronaridine, and mono-Mannich antimalarial agents containing a 5′-chlorophenyl group (tebuquine and 5′-ClPAQ). Chemical substitution at the C-5′ position also resulted in compounds which underwent slower elimination (<5% of the dose excreted into bile and urine, compared with 50% for amodiaquine) and increased levels of accumulation in tissue (10% of the dose in the liver at 48 h compared with 1% with amodiaquine). This may be due to an increase in either the lipophilicity or the basicity of the analogs and may reflect the lack of metabolic clearance for these compounds. The alteration in the disposition following the introduction of the C-5′ substituent resulted in an increased duration of antimalarial activity in the mouse compared with that for amodiaquine. While this is desirable in the treatment of malaria, repeated administration for prophylaxis may induce toxicity through accumulation. Therefore, by simple chemical modification it is possible to block the bioactivation of amodiaquine while maintaining and in some cases extending the duration of antimalarial activity.
Activity of Liposomal Amphotericin B with Prolonged Circulation in Blood versus Those of AmBisome and Fungizone against Intracellular
Candida albicans
in Murine Peritoneal Macrophages
Authors: van Etten Els W. M. , van Vianen Wim , Hak Janneke , Bakker-Woudenberg Irma A. J. M. 
Published: October 2018

ABSTRACT

Activity against intracellular
Candida albicans
was assessed in
C. albicans
-infected murine peritoneal macrophages exposed to long-circulating pegylated amphotericin B liposomes (PEG-AMB-LIP), AmBisome, or Fungizone. The level of antifungal activity of Fungizone is much higher than that of AmBisome or PEG-AMB-LIP, while PEG-AMB-LIP and AmBisome show equivalent activity levels. Previous exposure of uninfected macrophages to PEG-AMB-LIP or AmBisome is advantageous for intracellular antifungal activity.
Mixture-Based Heterocyclic Combinatorial Positional Scanning Libraries: Discovery of Bicyclic Guanidines Having Potent Antifungal Activities against
Candida albicans
and
Cryptococcus neoformans
Authors: Blondelle Sylvie E. , Crooks Ema , Ostresh John M. , Houghten Richard A. 
Published: October 2018

ABSTRACT

A mixture-based synthetic combinatorial library of more than 100,000 bicyclic guanidines was generated in a positional scanning format and assayed for activity against
Candida albicans
. Potent individual bicyclic guanidines were directly identified following the screening of the library. Time-kill curve studies indicated bactericidal activities for the individual bicyclic guanidines. These compounds also showed potent activity against
Cryptococcus neoformans
. These studies demonstrate the value of using mixture-based combinatorial positional scanning libraries made up of heterocyclic compounds for the rapid identification of novel classes of antifungal compounds.
Detection of a Streptomycin/Spectinomycin Adenylyltransferase Gene (
aadA
) in
Enterococcus faecalis
Authors: Clark Nancye C. , Olsvik Ørjan , Swenson Jana M. , Spiegel Carol A. , Tenover Fred C. 
Published: October 2018

ABSTRACT

Genes encoding streptomycin/spectinomycin adenylyltransferases [ANT(3")(9)] have been reported to exist in gram-negative organisms and
Staphylococcus aureus
. During a study of high-level aminoglycoside resistance in enterococci, we encountered an isolate of
Enterococcus faecalis
that was streptomycin resistant but did not appear to contain the 6′-adenylyltransferase gene (
aadE
) when examined by PCR with specific primers. Phosphocellulose paper binding assays indicated the presence of an ANT(3")(9) enzyme. Streptomycin and spectinomycin MICs of 4,000 and 8,000 μg/ml, respectively, were observed for the isolate. PCR primers corresponding to a highly conserved region of the
aadA
gene were used to amplify a specific 284-bp product. The product hybridized with a digoxigenin-labeled PCR product from
E. coli
C600(pHP45Ω) known to contain the
aadA
gene. The
aadA
gene was transferred via filter matings from the
E. faecalis
donor to
E. faecalis
JH2-2. PCR primers designed for analysis of integrons were used to amplify a 1-kb product containing the
aadA
gene, which was cloned into the vector pCRII and transformed into
Escherichia coli
DH5-α competent cells.
d
-Rhodamine dye terminator cycle sequencing was used to determine the gene sequence, which was compared to previously reported sequences of
aadA
genes. We found the
aadA
gene in
E. faecalis
to be identical to the
aadA
genes reported by Sundström et al. for
E. coli
plasmid R6-5 (L. Sundström, P. Rådström, G. Swedberg, and O. Sköld, Mol. Gen. Genet. 213:191–201, 1988), by Fling et al. for the
aadA
within transposon Tn
7
(M. E. Fling, J. Kopf, and C. Richards, Nucleic Acids Res. 13:7095–7106, 1985), and by Hollingshead and Vapnek for
E. coli
R538-1 (S. Hollingshead and D. Vapnek, Plasmid 13:17–30, 1985). Previous reports of the presence of the
aadA
gene in enterococci appear to be erroneous and probably describe an
aadE
gene, since the isolates were reported to be susceptible to spectinomycin.
ADP-Ribosylation as an Intermediate Step in Inactivation of Rifampin by a Mycobacterial Gene
Authors: Quan Selwyn , Imai Tamae , Mikami Yuzuru , Yazawa Katsukiyo , Dabbs Eric R. , Morisaki Naoko , Iwasaki Shigeo , Hashimoto Yuichi , Furihata Kazuo 
Published: October 2018

ABSTRACT

Mycobacterium smegmatis
DSM43756 inactivates rifampin, and the inactivated antibiotic product recovered from culture medium was ribosylated on the 23-OH group. To study this process, the gene responsible for the inactivation was expressed at high levels by the
lac
promoter in
Escherichia coli
conferring resistance to >500 μg of antibiotic per ml. Cell homogenates generated a novel derivative designated RIP-TAs; in this study, we determined that RIP-TAs is 23-(
O
-ADP-ribosyl)rifampin. Our results indicated that RIP-TAs is an intermediate in the pathway leading to ribosylated rifampin and that the previously characterized gene encodes a mono(ADP-ribosyl)transferase which, however, shows no sequence similarity to other enzymes of this class.
Mechanism of Action and In Vitro Activity of 1′,3′-Dioxolanylpurine Nucleoside Analogues against Sensitive and Drug-Resistant Human Immunodeficiency Virus Type 1 Variants
Authors: Gu Zhengxian , Wainberg Mark A. , Nguyen-Ba Nghe , L’Heureux Lucille , de Muys Jean-Marc , Bowlin Terry L. , Rando Robert F. 
Published: October 2018

ABSTRACT

(−)-β-
d
-1′,3′-Dioxolane guanosine (DXG) and 2,6-diaminopurine (DAPD) dioxolanyl nucleoside analogues have been reported to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1). We have recently conducted experiments to more fully characterize their in vitro anti-HIV-1 profiles. Antiviral assays performed in cell culture systems determined that DXG had 50% effective concentrations of 0.046 and 0.085 μM when evaluated against HIV-1
IIIB
in cord blood mononuclear cells and MT-2 cells, respectively. These values indicate that DXG is approximately equipotent to 2′,3′-dideoxy-3′-thiacytidine (3TC) but 5- to 10-fold less potent than 3′-azido-2′,3′-dideoxythymidine (AZT) in the two cell systems tested. At the same time, DAPD was approximately 5- to 20-fold less active than DXG in the anti-HIV-1 assays. When recombinant or clinical variants of HIV-1 were used to assess the efficacy of the purine nucleoside analogues against drug-resistant HIV-1, it was observed that AZT-resistant virus remained sensitive to DXG and DAPD. Virus harboring a mutation(s) which conferred decreased sensitivity to 3TC, 2′,3′-dideoxyinosine, and 2′,3′-dideoxycytidine, such as a 65R, 74V, or 184V mutation in the viral reverse transcriptase (RT), exhibited a two- to fivefold-decreased susceptibility to DXG or DAPD. When nonnucleoside RT inhibitor-resistant and protease inhibitor-resistant viruses were tested, no change in virus sensitivity to DXG or DAPD was observed. In vitro drug combination assays indicated that DXG had synergistic antiviral effects when used in combination with AZT, 3TC, or nevirapine. In cellular toxicity analyses, DXG and DAPD had 50% cytotoxic concentrations of greater than 500 μM when tested in peripheral blood mononuclear cells and a variety of human tumor and normal cell lines. The triphosphate form of DXG competed with the natural nucleotide substrates and acted as a chain terminator of the nascent DNA. These data suggest that DXG triphosphate may be the active intracellular metabolite, consistent with the mechanism by which other nucleoside analogues inhibit HIV-1 replication. Our results suggest that the use of DXG and DAPD as therapeutic agents for HIV-1 infection should be explored.
Plasmid-Mediated Resistance to Thrombin-Induced Platelet Microbicidal Protein in Staphylococci: Role of the
qacA
Locus
Authors: Kupferwasser Leon Iri , Skurray Ronald A. , Brown Melissa H. , Firth Neville , Yeaman Michael R. , Bayer Arnold S. 
Published: October 2018

ABSTRACT

Thrombin-induced platelet microbicidal protein 1 (tPMP-1) is a small, cationic peptide released from rabbit platelets following thrombin stimulation. In vitro resistance to this peptide among strains of
Staphylococcus aureus
correlates with the survival advantage of such strains at sites of endothelial damage in humans as well as in experimental endovascular infections. The mechanisms involved in the phenotypic resistance of
S. aureus
to tPMP-1 are not fully delineated. The plasmid-encoded staphylococcal gene
qacA
mediates multidrug resistance to multiple organic cations via a proton motive force-dependent efflux pump. We studied whether the
qacA
gene might also confer resistance to cationic tPMP-1. Staphylococcal plasmids encoding
qacA
were found to confer resistance to tPMP-1 in an otherwise susceptible parental strain. Deletions which removed the region containing the
qacA
gene in the
S. aureus
multiresistance plasmid pSK1 abolished tPMP-1 resistance. Resistance to tPMP-1 in the
qacA
-bearing strains was inoculum independent but peptide concentration dependent, with the level of resistance decreasing at higher peptide concentrations for a given inoculum. There was no apparent cross-resistance in
qacA
-bearing strains to other endogenous cationic antimicrobial peptides which are structurally distinct from tPMP-1, including human neutrophil defensin 1, protamine, or the staphylococcal lantibiotics pep5 and nisin. These data demonstrate that the staphylococcal multidrug resistance gene
qacA
also mediates in vitro resistance to cationic tPMP-1.
Pharmacokinetics and Absolute Bioavailability of Ribavirin in Healthy Volunteers as Determined by Stable-Isotope Methodology
Authors: Preston Sandra L. , Drusano George L. , Glue Paul , Nash Jacqueline , Gupta S. K. , McNamara P. 
Published: October 2018

ABSTRACT

Ribavirin has recently been demonstrated to have efficacy in combination with alpha interferon for treatment of relapsed hepatitis C. The marked improvement in the response rate after treatment with the combination regimen (10-fold higher versus that from monotherapy with alpha interferon) highlights the importance of determining the absolute bioavailability of ribavirin as a first step in beginning to investigate the pharmacodynamics of the combination. The objective of this study was to determine the absolute bioavailability of ribavirin with an intravenous formulation containing ribavirin labeled with the stable isotope
13
C
3
(
13
C
3
-ribavirin) and unlabeled oral ribavirin. Six healthy volunteers received 150 mg of intravenous
13
C
3
-ribavirin followed 1 h later by a 400-mg oral dose of ribavirin. Samples of blood and urine were collected up to 169 h postdosing. Concentrations of
13
C
3
-ribavirin and unlabeled ribavirin were determined by a high-performance liquid chromatography tandem mass spectrometric method. All plasma and urine data were comodeled for labeled and unlabeled ribavirin by using both the two- and three-compartment models in the program ADAPT II. A three-compartment model was chosen for the pharmacokinetic analysis with the Akaike Information Criterion. The mean maximum concentrations of drug in plasma for intravenous and oral ribavirin were 4,187 and 638 ng/ml, respectively. The mean bioavailability was 51.8% ± 21.8%, and the mean γ-phase half-life was 37.0 ± 14.2 h. The mean renal clearance, metabolic clearance, and volume of distribution of the central compartment were 6.94 liters/h, 18.1 liters/h, and 17.8 liters, respectively. The use of the stable-isotope methodology has provided the best estimate of the absolute bioavailability of ribavirin that is currently available, as there was neither a period bias nor a washout effect to confound the data. The study demonstrated that the mean bioavailability for a 400-mg dose of ribavirin was 52%, which is higher than that previously reported in other investigations.
Patterns of Macrolide Resistance Determinants among Community-Acquired
Streptococcus pneumoniae
Isolates over a 5-Year Period of Decreased Macrolide Susceptibility Rates
Authors: Oster Philipp , Zanchi Alessandra , Cresti Stefania , Lattanzi Maria , Montagnani Francesca , Cellesi Carla , Rossolini Gian Maria 
Published: October 2018

ABSTRACT

Erythromycin resistance rates were found to be increased, from 7.1 in 1993 to 32.8% in 1997, among community-acquired
Streptococcus pneumoniae
isolates from the Siena area of central Italy. Most of the erythromycin-resistant isolates carried
ermAM
determinants and were also resistant to josamycin and clindamycin, whereas a minority (5.8%) carried
mefA
determinants and remained susceptible to the latter drugs.
In Vitro Susceptibilities of
Mycoplasma hominis
to Six Fluoroquinolones as Determined by E Test
Authors: Waites Ken B. , Canupp Kay C. , Kenny George E. 
Published: October 2018

ABSTRACT

Twenty isolates of
Mycoplasma hominis
were tested for their susceptibility to six fluoroquinolones by the E test. The MICs at which 90% of the isolates were inhibited (in micrograms per milliliter) were as follows: sparfloxacin, 0.031; clinafloxacin, moxifloxacin, and trovafloxacin, 0.063; levofloxacin, 0.25; and ciprofloxacin, 0.5. Increasing the amount of inoculum or incubation in CO
2
elevated MICs by ≤1 dilution. E tests produce fluoroquinolone MICs comparable to those obtained by agar and microbroth dilution for
M. hominis.
Drug Tolerance in
Mycobacterium tuberculosis
Authors: Wallis Robert S. , Patil Shripad , Cheon Seon-Hee , Edmonds Kay , Phillips Manijeh , Perkins Mark D. , Joloba Moses , Namale Alice , Johnson John L. , Teixeira Lucileia , Dietze Reynaldo , Siddiqi Salman , Mugerwa Roy D. , Eisenach Kathleen , Ellner Jerrold J. 
Published: October 2018

ABSTRACT

Although
Mycobacterium tuberculosis
is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (
P
< 0.001). Isolates from subjects who had relapses (
n
= 2) or in whom persistence was prolonged (
n
= 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (
P
< 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (
P
= 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (
P
< 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis.
Isolation of Polymyxin B-Susceptible Mutants of
Burkholderia pseudomallei
and Molecular Characterization of Genetic Loci Involved in Polymyxin B Resistance
Authors: Burtnick Mary N. , Woods Donald E. 
Published: October 2018

ABSTRACT

Burkholderia pseudomallei
is a gram-negative bacterium that causes the disease known as melioidosis. This pathogen is endemic to Southeast Asia and northern Australia and is particularly problematic in northeastern Thailand. It has been previously reported that
B. pseudomallei
is resistant to the killing action of cationic antimicrobial peptides, including human neutrophil peptide, protamine sulfate, poly-
l
-lysine, magainins, and polymyxins. Recently, we have also found that the virulent clinical isolate
B. pseudomallei
1026b is capable of replicating in media containing polymyxin B at concentrations of >100 mg/ml. In order to identify genetic loci that are associated with this particular resistance phenotype, we employed a Tn
5
-OT182 mutagenesis system in coordination with a replica plating screen to isolate polymyxin B-susceptible mutants. Of the 17,000 Tn
5
-OT182 mutants screened via this approach, five polymyxin B-susceptible mutants were obtained. Three of these mutants harbored Tn
5
-OT182 insertions within a genetic locus demonstrating strong homology to the
lytB
gene present in other gram-negative bacteria. Of the remaining two mutants, one contained a transposon insertion in a locus involved in lipopolysaccharide core biosynthesis (
waaF
), while the other contained an insertion in an open reading frame homologous to UDP-glucose dehydrogenase genes. Isogenic mutants were also constructed via allelic exchange and used in complementation analysis studies to further characterize the relative importance of each of the various genetic loci with respect to the polymyxin B resistance phenotype exhibited by
B. pseudomallei
1026b.
Oligonucleotides Tethered to a Short Polyguanylic Acid Stretch Are Targeted to Macrophages: Enhanced Antiviral Activity of a Vesicular Stomatitis Virus-Specific Antisense Oligonucleotide
Authors: Prasad Vikram , Hashim Shehla , Mukhopadhyay Amitabha , Basu Sandip K. , Roy Rajendra P. 
Published: October 2018

ABSTRACTThe poor membrane permeability of oligonucleotides is one of the major problems of antisense technology. Here we report the construction of designer oligonucleotides for targeted delivery to macrophages. The oligonucleotides tethered to a 10-mer poly(G) sequence at their 3′ ends were recognized by scavenger receptors on macrophages and were taken up about 8- to 10-fold as efficiently as those oligonucleotides that either lacked a poly(G) tail or that contained a 10-mer poly(C) tail instead of the poly(G) tail. The enhanced uptake of poly(G) constructs was inhibited in the presence of poly(G) and other known ligands of the scavenger receptor. The bioefficacy of poly(G)-mediated targeting of antisense oligonucleotides (ANS) was demonstrated by using vesicular stomatitis virus (VSV) as a model system. The ability of ANS directed against the translation initiation site of N protein mRNA of VSV to inhibit virus replication was assessed. The ANS with the 10-mer poly(G) sequences (ANS-G) brought about significant inhibition of VSV replication in J774E cells (a murine monocyte/macrophage cell line) and Chinese hamster ovary (CHO) cell transfectants expressing scavenger receptors. The ANS lacking a 10-mer poly(G) stretch were ineffective. The inhibition of VSV replication due to ANS-G was completely abrogated in the presence of 10-mer poly(G), indicating that the antisense effect of the ANS-G molecule was a consequence of scavenger receptor-mediated enhanced uptake. Importantly, antisense molecules linked exclusively by natural phosphodiester bonds were as bioeffective as those synthesized with a mixed backbone of phosphodiester and phosphorothioate. Taken together, these results suggest that macrophage-directed designer ANS against infective agents may simply be obtained by adding a short stretch of guanylic acid sequence to the desired specific ANS during solid-phase synthesis. This nucleic acid-based strategy, which utilizes homogeneous preparation of ANS, may find applications in directed manipulation of macrophage metabolism for a variety of purposes as well as in therapy of a broad spectrum of macrophage-related disorders amenable to the antisense approach.
Activities of Gemifloxacin (SB 265805, LB20304) Compared to Those of Other Oral Antimicrobial Agents against Unusual Anaerobes
Authors: Goldstein Ellie J. C. , Citron Diane M. , Vreni Merriam C. , Tyrrell Kerin , Warren Yumi 
Published: October 2018

ABSTRACT

The activities of gemifloxacin (SB 265805, LB20304) and comparator agents were determined by an agar dilution method against 419 clinical strains of less-commonly identified species of anaerobes. Gemifloxacin was generally more active than trovafloxacin against gram-positive strains by one to two dilutions. Peptostreptococci (
Peptostreptococcus asaccharolyticus
,
Peptostreptococcus magnus
,
Peptostreptococcus micros
, and
Peptostreptococcus prevotii
) and
Porphyromonas
spp. (
Porphyromonas asaccharolytica
,
Porphyromonas canoris
,
Porphyromonas gingivalis
, and
Porphyromonas macacae
) were all susceptible to ≤0.25 μg of gemifloxacin per ml. The MICs of gemifloxacin at which 90% of the following strains were inhibited (MIC
90
s) were ≤2 μg/ml:
Actinomyces israelii
,
Actinomyces odontolyticus
,
Clostridium innocuum
,
Clostridium clostridioforme
,
Anaerobiospirillum
spp.,
Bacteroides tectum
,
Bacteroides ureolyticus
,
Bacteroides gracilis
(now
Campylobacter gracilis
),
Prevotella intermedia
,
Prevotella heparinolytica
, and the
Prevotella oris-buccae
group.
Fusobacterium naviforme
and
Fusobacterium necrophorum
were also susceptible to ≤2 μg of gemifloxacin per ml, while
Fusobacterium varium
strains exhibited a bimodal pattern; the other
Fusobacterium
species, such as
Fusobacterium ulcerans
and
Fusobacterium russii
, as well as
Veillonella
spp., the
Prevotella melaninogenica
group,
Prevotella bivia
,
Clostridium difficile
, and
Bilophila wadsworthia
were relatively resistant to gemifloxacin (MIC
90
s, ≥4 μg/ml).