bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Human Immunodeficiency Virus Type 1 Infection in SCID-hu Thy/Liv Mice by the G-Quartet-Forming Oligonucleotide, ISIS 5320
Authors: Stoddart Cheryl A. , Rabin Linda , Hincenbergs Mara , Moreno Mary e. , Linquist-Stepps Valerie , Leeds Janet M. , Truong Lo Anne , Wyatt J. R. , Ecker David J. , McCune Joseph M. 
Published: October 2018

ABSTRACT
Viral replication was inhibited in a dose-dependent manner after administration of the phosphorothioate oligonucleotide TTGGGGTT (ISIS 5320) to human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu Thy/Liv mice. Potent in vivo antiviral activity was observed against the T-cell-tropic molecular clone NL4-3; the agent was found to have weak activity against one primary HIV-1 isolate, and the agent was inactive against a second primary isolate.
In Vitro Activities of the Ketolide HMR 3647 against Recent Gram-Positive Clinical Isolates and
Haemophilus influenzae
Authors: Barry Arthur L. , Fuchs Peter C. , Brown Steven D. 
Published: October 2018

ABSTRACT

The ketolide HMR 3647 (previously RU 66647) was evaluated against 2,563 recent clinical isolates of gram-positive pathogens and 200
Haemophilus influenzae
isolates. HMR 3647 was active against macrolide-resistant streptococci, including pneumococci, but was not active against macrolide- or lincosamide-resistant staphylococci. Against
H. influenzae
, the potency of HMR 3647 was similar to that of azithromycin.
Fungal β-Tubulin, Expressed as a Fusion Protein, Binds Benzimidazole and Phenylcarbamate Fungicides
Authors: Hollomon Derek W. , Butters Jenny A. , Barker Helen , Hall Len 
Published: October 2018

ABSTRACT

Benzimidazoles are important antitubulin agents used in veterinary medicine and plant disease control. Resistance is a practical problem correlated with single amino acid changes in β-tubulin and is often linked to greater sensitivity to phenylcarbamates. This negative cross-resistance creates opportunities for durable antiresistance strategies. Attempts to understand the molecular basis of benzimidazole resistance have been hampered by the inability to purify tubulin from filamentous fungi. We have overcome some of these problems by expressing β-tubulin as a fusion with a maltose binding protein. This fusion protein is soluble, and we confirm for the first time using a gel filtration assay that benzimidazoles indeed bind to β-tubulin. This binding is reduced by the mutation Glu
198
→Gly
198
, which also confers resistance. Binding of phenylcarbamates is the complete opposite, reflecting their biological activity and the negative cross-resistance. This suggests that the fungicide binding sites fold correctly in the fusion protein.
Sparfloxacin Resistance in Clinical Isolates of
Streptococcus pneumoniae
: Involvement of Multiple Mutations in
gyrA
and
parC
Genes
Authors: Taba Hideki , Kusano Nobuchika 
Published: October 2018

ABSTRACT

Antimicrobial susceptibility testing revealed among 150 clinical isolates of
Streptococcus pneumoniae
4 pneumococcal isolates with resistance to fluoroquinolones (MIC of ciprofloxacin, ≥32 μg/ml; MIC of sparfloxacin, ≥16 μg/ml). Gene amplification and sequencing analysis of
gyrA
and
parC
revealed nucleotide changes leading to amino acid substitutions in both GyrA and ParC of all four fluoroquinolone-resistant isolates. In the case of strains 182 and 674 for which sparfloxacin MICs were 16 and 64 μg/ml, respectively, nucleotide changes were detected at codon 81 in
gyrA
and codon 79 in
parC
; these changes led to an Ser→Phe substitution in GyrA and an Ser→Phe substitution in ParC. Strains 354 and 252, for which sparfloxacin MICs were 128 μg/ml, revealed multiple mutations in both
gyrA
and
parC
. These strains exhibited nucleotide changes at codon 85 leading to a Glu→Lys substitution in GyrA, in addition to Ser-79→Tyr and Lys-137→Asn substitutions in ParC. Moreover, strain 252 showed additional nucleotide changes at codon 93, which led to a Trp→Arg substitution in GyrA. These results suggest that sparfloxacin resistance could be due to the multiple mutations in GyrA and ParC. However, it is possible that other yet unidentified mutations may also be involved in the high-level resistance to fluoroquinolones in
S. pneumoniae
.
Molecular Mode of Action of the Antifungal β-Amino Acid BAY 10-8888
Authors: Ziegelbauer Karl , Babczinski Peter , Schönfeld Wolfgang 
Published: October 2018

ABSTRACT

BAY 10-8888 is a cyclic β-amino acid that is related to cispentacin and that has antifungal activity.
Candida albicans
cells accumulated BAY 10-8888 intracellularly to a concentration about 200 that in the medium when grown in media with a variety of nitrogen sources. In complex growth medium, BAY 10-8888 transport activity was markedly reduced and was paralleled by a decrease in its antifungal activity. Uptake of BAY 10-8888 was mediated by an H
+
-coupled amino acid transporter with specificity for branched-chain amino acids (isoleucine, leucine, and valine) and showed a

K
T

(Michaelis constant of the transport reaction) of 0.95 mM and a
V
max
of 18.9 nmol × min
−1
× 10
7
cells
−1
. Similar to the transport of natural amino acids in
Saccharomyces cerevisiae
, the transport of BAY 10-8888 into the cell was unidirectional. Efflux occurred by diffusion and was not carrier mediated. Inside the cell BAY 10-8888 inhibited specifically isoleucyl-tRNA synthetase, resulting in inhibition of protein synthesis and cell growth. Intracellular isoleucine reversed BAY 10-8888-induced growth inhibition. BAY 10-8888 was not incorporated into proteins. BAY 10-8888 inhibited isoleucyl-tRNA synthetase with the same concentration dependency as protein biosynthesis in intact cells assuming 200-fold accumulation.
In Vitro Effectiveness of Povidone-Iodine on
Acanthamoeba
Isolates from Human Cornea
Authors: Gatti Simonetta , Cevini Claudia , Bruno Antonella , Penso Gabriella , Rama Paolo , Scaglia Massimo 
Published: October 2018

ABSTRACT

Acanthamoeba
keratitis is a severe ocular infection secondary to accidental macro- or microscopic trauma of the cornea. Starting in 1985, a dramatic increase of this infection was recorded along with the spread of contact lens use. This protozoal disease is difficult to treat because of the scarcity of efficacious topical and systemic drugs. We evaluated the in vitro effectiveness of povidone-iodine (PVP-I [Betadine]), an agent with broad antibacterial and antiviral activity, compared to that of chlorhexidine (CXD), a cationic antiseptic, on
Acanthamoeba
isolates from patients with amebic keratitis. The results showed that PVP-I solution from 0.5 to 2.5% has a better antiamebic activity both on trophic and cystic stages of
Acanthamoeba
spp. than does CXD.
Effects of α-Thalassemia on Pharmacokinetics of the Antimalarial Agent Artesunate
Authors: Ittarat Wanida , Looareesuwan Sornchai , Pootrakul Pensri , Sumpunsirikul Petchmanee , Vattanavibool Phantip , Meshnick Steven R. 
Published: October 2018

ABSTRACT

Thalassemia is common in Southeast Asia, where artemisinin derivatives are frequently used in the treatment of malaria. It has been previously reported that artemisinin derivatives can be concentrated by uninfected thalassemic erythrocytes in vitro but not by normal erythrocytes. As a follow-up to this report, we studied the antimalarial kinetics of intravascular artesunate (2.4 mg/kg of body weight) in 10 persons with normal hemoglobins and in 10 patients with thalassemia (2 with α-thalassemia type 1–hemoglobin Constant Spring and 8 with α-thalassemia type 1–α-thalassemia type 2). Concentrations of artesunate and its active metabolites in plasma were measured by bioassay and expressed relative to those of dihydroartemisinin, the major biologically active metabolite. Concentrations of intravascular artesunate in plasma peaked in both the normal individuals and the thalassemic individuals 15 min after injection (the first time point). Plasma drug concentrations at all time intervals, except that at 1 h, were significantly higher in thalassemic subjects than in normal subjects (
P
< 0.05). The area under the concentration-time curve was 9-fold higher (
P
< 0.001) and the volume of distribution at steady state was 15-fold lower (
P
< 0.001) in thalassemic than in normal subjects. In light of the potential neurotoxicity of artemisinin derivatives, these results suggest that thalassemic subjects may need a drug administration regimen different from that of normal patients.
Safety, Pharmacokinetics, and Antiretroviral Activity of Intravenous 9-[2-(
R
)-(Phosphonomethoxy)propyl]adenine, a Novel Anti-Human Immunodeficiency Virus (HIV) Therapy, in HIV-Infected Adults
Authors: Deeks Steven G. , Barditch-Crovo Patricia , Lietman Paul S. , Hwang Frances , Cundy Kenneth C. , Rooney James F. , Hellmann Nicholas S. , Safrin Sharon , Kahn James O. 
Published: October 2018

ABSTRACT

9-[2-(
R
)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of ≥200 cells/mm
3
and plasma HIV RNA levels of ≥10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of PMPA or placebo was administered by intravenous infusion. Beginning on study day 8, PMPA or placebo was administered once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 ± 0.9 and 9.1 ± 2.1 μg/ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At 3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log
10
median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were −1.1, −0.6, and 0.1 log
10
in the 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively. Following the final dose in the 3-mg/kg/day cohort, the reduction in HIV RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.
Safety, Tolerance, and Pharmacokinetics of a Small Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in Neutropenic Patients
Authors: Walsh Thomas J. , Yeldandi Vijay , McEvoy Maureen , Gonzalez Corina , Chanock Stephen , Freifeld Alison , Seibel Nita I. , Whitcomb Patricia O. , Jarosinski Paul , Boswell Garry , Bekersky Ihor , Alak Ala , Buell Donald , Barret John , Wilson Wyndham 
Published: October 2018

ABSTRACT

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm
3
) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.
Evaluation of Several Dosing Regimens of Cefepime, with Various Simulations of Renal Function, against Clinical Isolates of
Pseudomonas aeruginosa
in a Pharmacodynamic Infection Model
Authors: Cappelletty Diane M. 
Published: October 2018

ABSTRACT

The objectives of this study were as follows: (i) to examine the killing activity of 2-g doses of cefepime against two clinical isolates (mucoid and nonmucoid) of
Pseudomonas aeruginosa
in a pharmacodynamic in vitro infection model, (ii) to compare the percentage of time above the MIC (T > MIC) for each of the regimens against
P. aeruginosa
, and (iii) to evaluate the area under the bactericidal curve for each regimen. Cefepime was administered at intervals of 8, 12, and 24 h with and without tobramycin, and two different levels of renal function were simulated: normal (creatinine clearance [CL
CR
] = 90 ml/min) and decreased (CR
CL
= 60 ml/min). Also, the killing activity of cefepime with and without tobramycin was compared to the killing activity of ceftazidime (2 g every 8 h) with and without tobramycin. The T > MIC was 100% in the central chamber except for the regimen in which cefepime was administered every 12 h and the CL
CR
was 90 ml/min, which provided concentrations above the MIC for 92% of the dosing interval against the C31 (mucoid; MIC of cefepime, 4 μg/ml) isolate and for 75% of the interval against the C34 (nonmucoid; MIC of cefepime, 8 μg/ml) isolate. All cefepime and ceftazidime monotherapy simulations resulted in 99.9% killing of the nonmucoid isolate within 4 to 8 h and within 4 to 6 h, respectively. Against the mucoid isolate, 99.9% killing was achieved only with combination therapy. The results of this study indicate that cefepime dosed at 2 g every 12 h under conditions of normal renal function and every 24 h with decreased creatinine clearance (60 ml/min) is effective both as monotherapy and in combination therapy against a nonmucoid strain of
P. aeruginosa
. With cefepime MICs of 4 and 8 μg/ml, the single-agent regimens provided T > MIC values in the central chamber for 92 and ≥75% of the dosing interval against the mucoid and nonmucoid isolates, respectively. Cefepime dosed at 2 g every 12 h, with a creatinine clearance of 90 ml/min, and every 24 h, with a creatinine clearance of 60 ml/min, resulted in killing activity equivalent to that of ceftazidime dosed at 2 g every 8 h. None of the monotherapies provided adequate killing of the mucoid strain of
P. aeruginosa
despite drug concentrations being above the MIC for ≥92% of all dosing intervals. Finally, combination therapy with tobramycin and either cefepime or ceftazidime enhanced the killing of both the mucoid and nonmucoid
P. aeruginosa
isolates.
Pharmacokinetics of Quinupristin-Dalfopristin in Continuous Ambulatory Peritoneal Dialysis Patients
Authors: Johnson Curtis A. , Taylor Claude A. , Zimmerman Stephen W. , Bridson William E. , Chevalier Paul , Pasquier Olivier , Baybutt Robert I. 
Published: October 2018

ABSTRACT

Quinupristin-dalfopristin may be useful for treatment of organisms causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci, methicillin-resistant
Staphylococcus aureus
, and vancomycin-resistant enterococci. The pharmacokinetic profiles of single intravenous doses of this combination streptogramin antibiotic of 7.5 mg/kg of body weight were characterized for eight noninfected patients receiving continuous ambulatory peritoneal dialysis. Comparison was made to pharmacokinetic profiles determined for eight healthy volunteers matched by age, sex, and race. Drug was measured in dialysate up to 6 h following the dose. Plasma and dialysate were assayed for parent compounds and metabolites. Mean pharmacokinetic parameters were compared between groups. No statistically significant differences were observed between groups for maximal concentrations in plasma, times to maximal concentration, areas under the curve, distribution volumes, rates of total body clearance, or half-lives in plasma for quinupristin and dalfopristin. No statistically significant differences were observed in maximal concentrations in plasma, times to maximal concentration, areas under the curve, or half-lives for cysteine, the glutathione conjugates of quinupristin, or the pristinamycin IIA metabolite of dalfopristin. The measurements in dialysate of the parent and most metabolites were below the expected MICs. Dialysis clearance was insignificant. Quinupristin-dalfopristin was well tolerated in both groups, causing only mild adverse events that resolved prior to discharge from the study. The disposition of quinupristin, dalfopristin, or their primary metabolites following a single dose was unaltered in patients receiving peritoneal dialysis. Intravenous dosing of this antibiotic combination is unlikely to be adequate for the treatment of peritonitis associated with peritoneal dialysis.
In Vitro Activities of Six New Fluoroquinolones against
Brucella melitensis
Authors: Trujillano-Martín Ignacio , García-Sánchez Enrique , Martínez Isaías Montes , Fresnadillo María José , García-Sánchez José Elías , García-Rodríguez José Ángel 
Published: October 2018

ABSTRACT

We have tested the in vitro activities of eight fluoroquinolones against 160
Brucella melitensis
strains. The most active was sitafloxacin (MIC at which 90% of the isolates are inhibited [MIC
90
], 0.12 μg/ml). In decreasing order, the activities (MIC
90
s) of the rest of the tested fluoroquinolones were as follows: levofloxacin, 0.5 μg/ml; ciprofloxacin, trovafloxacin, and moxifloxacin, 1 μg/ml; and ofloxacin, grepafloxacin, and gatifloxacin, 2 μg/ml.
Molecular Basis of Rifampin Resistance inStreptococcus pneumoniae
Authors: Padayachee Thanugarani , Klugman Keith P. 
Published: October 2018

ABSTRACTRifampin resistance among South African clinical isolates ofStreptococcus pneumoniaewas shown to be due to missense mutations within therpoBgene. Sequence analysis of 24 rifampin-resistant isolates revealed the presence of mutations within cluster I as well as novel mutations in an area designated pneumococcus cluster III. Of the 24 isolates characterized, only 1 resistant isolate did not contain any mutations in the regions sequenced. Either the cluster I or the cluster III mutations separately conferred MICs of 32 to 128 μg/ml. Clinical isolate 55, for which the MIC was 256 μg/ml, was noted to contain 9 of the 10 mutations identified, which included the cluster I and cluster III mutations. As inEscherichia coli, it is possible that cluster I (amino acids 406 to 434) and cluster III (amino acids 523 to 600) ofS. pneumoniaeinteract to form part of the antibiotic binding site, thus accounting for the very high MIC observed for isolate 55. PCR products containing cluster I or cluster III mutations were able to transform rifampin-susceptibleS. pneumoniaeto resistance. Although many of the isolates studied displayed identical sequences, pulsed-field gel electrophoresis analysis revealed that the isolates were not of clonal origin.
Multiple Novel Inhibitors of the NorA Multidrug Transporter of
Staphylococcus aureus
Authors: Markham Penelope N. , Westhaus Eric , Klyachko Katya , Johnson Michael E. , Neyfakh Alex A. 
Published: October 2018

ABSTRACT

The multidrug transporter NorA contributes to the resistance of
Staphylococcus aureus
to fluoroquinolone antibiotics by promoting their active extrusion from the cell. Previous studies with the alkaloid reserpine, the first identified inhibitor of NorA, indicate that the combination of a chemical NorA inhibitor with a fluoroquinolone could improve the efficacy of this class of antibiotics. Since reserpine is toxic to humans at the concentrations required to inhibit NorA, we sought to identify new inhibitors of NorA that may be used in a clinical setting. Screening of a chemical library yielded a number of structurally diverse inhibitors of NorA that were more potent than reserpine. The new inhibitors act in a synergistic manner with the most widely used fluoroquinolone, ciprofloxacin, by substantially increasing its activity against both NorA-overexpressing and wild-type
S. aureus
isolates. Furthermore, the inhibitors dramatically suppress the emergence of ciprofloxacin-resistant
S. aureus
upon in vitro selection with this drug. Some of these new inhibitors, or their derivatives, may prove useful for augmentation of the antibacterial activities of fluoroquinolones in the clinical setting.
In Vitro Antiviral Activity of AG7088, a Potent Inhibitor of Human Rhinovirus 3C Protease
Authors: Patick A. K. , Binford S. L. , Brothers M. A. , Jackson R. L. , Ford C. E. , Diem M. D. , Maldonado F. , Dragovich P. S. , Zhou R. , Prins T. J. , Fuhrman S. A. , Meador J. W. , Zalman L. S. , Matthews D. A. , Worland S. T. 
Published: October 2018

ABSTRACTAG7088 is a potent, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (kobs/[I]} = 1,470,000 ± 440,000 M−1s−1for HRV 14) that was discovered by protein structure-based drug design methodologies. In H1-HeLa and MRC-5 cell protection assays, AG7088 inhibited the replication of all HRV serotypes (48 of 48) tested with a mean 50% effective concentration (EC50) of 0.023 μM (range, 0.003 to 0.081 μM) and a mean EC90of 0.082 μM (range, 0.018 to 0.261 μM) as well as that of related picornaviruses including coxsackieviruses A21 and B3, enterovirus 70, and echovirus 11. No significant reductions in the antiviral activity of AG7088 were observed when assays were performed in the presence of α1-acid glycoprotein or mucin, proteins present in nasal secretions. The 50% cytotoxic concentration of AG7088 was >1,000 μM, yielding a therapeutic index of >12,346 to >333,333. In a single-cycle, time-of-addition assay, AG7088 demonstrated antiviral activity when added up to 6 h after infection. In contrast, a compound targeting viral attachment and/or uncoating was effective only when added at the initiation of virus infection. Direct inhibition of 3C proteolytic activity in infected cells treated with AG7088 was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of radiolabeled proteins, which showed a dose-dependent accumulation of viral precursor polyproteins and reduction of processed protein products. The broad spectrum of antiviral activity of AG7088, combined with its efficacy even when added late in the virus life cycle, highlights the advantages of 3C protease as a target and suggests that AG7088 will be a promising clinical candidate.