bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of Action of the Mannopeptimycins, a Novel Class of Glycopeptide Antibiotics Active against Vancomycin-Resistant Gram-Positive Bacteria
Authors: Ruzin Alexey , Singh Guy , Severin Anatoly , Yang Youjun , Dushin Russell G. , Sutherland Alan G. , Minnick Albert , Greenstein Michael , May Michael K. , Shlaes David M. , Bradford Patricia A. 
Published: February 2004

ABSTRACT

The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C
55
-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.
Activity of Posaconazole Combined with Amphotericin B against
Aspergillus flavus
Infection in Mice: Comparative Studies in Two Laboratories
Authors: Najvar Laura K. , Cacciapuoti Anthony , Hernandez Steve , Halpern Judith , Bocanegra Rosie , Gurnani Maya , Menzel Frederick , Loebenberg David , Graybill John R. 
Published: February 2004

ABSTRACT

Posaconazole and/or amphotericin B was given to mice pretreated with a steroid and then infected by inhalation of
Aspergillus flavus
conidia. Two laboratories conducted studies using almost identical protocols to evaluate both survival and lung tissue burdens 8 days after infection. The results of the in vivo studies performed at both laboratories were consistent. We found that (i) up to 5 mg of amphotericin B per kg of body weight was poorly effective in treating invasive aspergillosis; (ii) posaconazole at 2 or 10 mg/kg/dose prolonged survival and reduced lung tissue CFU; and (iii) there was generally no antagonistic interaction of the drugs in combination, even when the experiments were designed to maximize the likelihood of antagonism. These studies do not confirm the antagonistic interaction of triazoles and polyenes reported by others.
Activities of Garenoxacin against Quinolone-Resistant
Streptococcus pneumoniae
Strains In Vitro and in a Mouse Pneumonia Model
Authors: Azoulay-Dupuis E. , Bédos J. P. , Mohler J. , Peytavin G. , Isturiz R. , Moine P. , Rieux V. , Cherbuliez C. , Péchère J. C. , Fantin B. , Köhler T. 
Published: February 2004

ABSTRACT

Garenoxacin is a novel des-F(6) quinolone with enhanced in vitro activities against both gram-positive and gram-negative bacteria. We compared the activity of garenoxacin with that of trovafloxacin (TVA) against
Streptococcus pneumoniae
, together with their efficacies and their capacities to select for resistant mutants, in a mouse model of acute pneumonia. In vitro, garenoxacin was more potent than TVA against wild-type
S. pneumoniae
and against a mutant with a single mutation (
parC
), a mutant with double mutations (
gyrA
and
parC
), and a mutant with triple mutations (
gyrA
,
parC
, and
parE
). Swiss mice were infected with 10
5
CFU of virulent, encapsulated
S. pneumoniae
strain P-4241 or its derived isogenic
parC
,
gyrA
,
gyrA parC
, and efflux mutants and 10
7
CFU of poorly virulent clinical strains carrying a
parE
mutation or
gyrA
,
parC
, and
parE
mutations. The drugs were administered six times, every 12 h, beginning at either 3 or 18 h postinfection. The pulmonary pharmacokinetic parameters in mice infected with strain P-4241 and treated with garenoxacin or TVA (25 mg/kg of body weight) were as follows: maximum concentration of drug in serum (
C
max
; 17.3 and 21.2 μg/ml, respectively),
C
max
/MIC ratio (288 and 170, respectively), area under the concentration-time curve (AUC; 48.5 and 250 μg · h/ml, respectively), and AUC/MIC ratio (808 and 2,000, respectively). Garenoxacin at 25 and 50 mg/kg was highly effective (survival rates, 85 to 100%) against the wild-type strain and mutants harboring a single mutation. TVA was as effective as garenoxacin against these strains. TVA at 200 mg/kg and garenoxacin at 50 mg/kg were ineffective against the mutant with the
parC
and
gyrA
double mutations and the mutant with the
gyrA
,
parC
, and
parE
triple mutations. The efficacy of garenoxacin was reduced only when strains bore several mutations for quinolone resistance.
Quantitative Evaluation of the Therapeutic Effects of Antibiotics Using Silkworms Infected with Human Pathogenic Microorganisms
Authors: Hamamoto Hiroshi , Kurokawa Kenji , Kaito Chikara , Kamura Koushirou , Manitra Razanajatovo Iony , Kusuhara Hiroyuki , Santa Tomofumi , Sekimizu Kazuhisa 
Published: February 2004

ABSTRACTThe injection of bacteria (Staphylococcus aureus,Stenotrophomonas maltophilia) or true fungi (Candida albicans,Candida tropicalis) that are pathogenic to humans into the silkworm hemolymph leads to death of the larvae within 2 days. Antibiotics used for clinical purposes have therapeutic effects on silkworms infected with these pathogens. The 50% effective doses obtained by injection into the silkworm hemolymph are consistent with those reported for mice. Injection of vancomycin and kanamycin into the silkworm hemolymph was effective, but oral administration was not. Chloramphenicol, which is effective by oral administration, appeared in the silkworm hemolymph soon after injection into the midgut, whereas vancomycin did not. Isolated midgut membranes were impermeable to vancomycin. Thus, the ineffectiveness of oral administration of vancomycin to silkworms is due to a lack of intestinal absorption.
Preclinical Pharmacology and Pharmacokinetics of GW433908, a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir
Authors: Furfine Eric S. , Baker Christopher T. , Hale Michael R. , Reynolds David J. , Salisbury Jo A. , Searle Andy D. , Studenberg Scott D. , Todd Dan , Tung Roger D. , Spaltenstein Andrew 
Published: February 2004

ABSTRACT

GW433908 is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of GW433908 is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl
3
) in pyridine. A single-dose pharmacokinetic study of GW433908 sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of GW433908 was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of GW433908 calcium salt in dogs and rats produced portal vein GW433908 concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, GW433908 had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that GW433908 is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, GW433908 was advanced to clinical development.
Disposition of Caspofungin: Role of Distribution in Determining Pharmacokinetics in Plasma
Authors: Stone Julie A. , Xu Xin , Winchell Gregory A. , Deutsch Paul J. , Pearson Paul G. , Migoya Elizabeth M. , Mistry Goutam C. , Xi Liwen , Miller Alisha , Sandhu Punam , Singh Romi , deLuna Florencia , Dilzer Stacy C. , Lasseter Kenneth C. 
Published: February 2004

ABSTRACT

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 μCi) of [
3
H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (
n
= 6) and plasma was collected over 26 weeks in study B (
n
= 7). Supportive data were obtained from a single-dose [
3
H]caspofungin tissue distribution study in rats (
n
= 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (
t
1/2
= 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ∼92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.
Quality Assurance Program for Clinical Measurement of Antiretrovirals: AIDS Clinical Trials Group Proficiency Testing Program for Pediatric and Adult Pharmacology Laboratories
Authors: Holland Diane T. , DiFrancesco Robin , Stone Judith , Hamzeh Fayez , Connor James D. , Morse Gene D. 
Published: February 2004

ABSTRACTClinical trials designed to compare antiretroviral regimens, investigate therapeutic drug monitoring, or measure pharmacometrics often include protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase inhibitors, requiring the measurement of these antiretrovirals in plasma. Within the adult and pediatric AIDS Clinical Trials Group (ACTG), a network of Pharmacology Support Laboratories (PSLs) is a component of the group laboratory infrastructure and conducts these types of pharmacologic assays. The adult ACTG has developed a comprehensive quality assurance program for the conduct of clinical pharmacology protocols, one component of which is the antiretroviral proficiency testing (PT) program that has been implemented between the adult and pediatric pharmacology laboratories of the ACTG. PT testing samples were prepared and distributed in July 2001, February 2002, and July 2002. High, medium, and low concentrations of PIs (indinavir, saquinavir, amprenavir, lopinavir, ritonavir, and nelfinavir) and NNRTIs (nevirapine and efavirenz) were added to drug-free EDTA plasma and distributed, on dry ice, to eight ACTG PSLs. One testing laboratory used liquid chromatography-tandem mass spectrometry, and seven used high-performance liquid chromatography-UV analysis. A result was considered acceptable if it was within 20% deviation of the assigned concentration. For all concentrations of PIs evaluated, 96% of samples tested (430 of 448 measurements) met the acceptance criteria. For both NNRTIs, 100% of samples tested (140 of 140 measurements) met the acceptance criteria. In conclusion, the PT program results presented demonstrate excellent interlaboratory agreement for all antiretrovirals tested and provide support for the merger of plasma concentration data among laboratories for large clinical trials.
Geldanamycin, a Ligand of Heat Shock Protein 90, Inhibits the Replication of Herpes Simplex Virus Type 1 In Vitro
Authors: Li Yu-Huan , Tao Pei-Zhen , Liu Yu-Zhen , Jiang Jian-Dong 
Published: February 2004

ABSTRACT

Geldanamycin (GA) is an antibiotic targeting the ADP/ATP binding site of heat shock protein 90 (Hsp90). In screening for anti-herpes simplex virus type 1 (HSV-1) candidates, we found GA active against HSV-1. HSV-1 replication in vitro was significantly inhibited by GA with an 50% inhibitory concentration of 0.093 μM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 μM. The therapeutic index of GA was over 3,700 (comparable to the results seen with acyclovir). GA did not inhibit HSV-1 thymidine kinase. Cells infected with HSV-1 demonstrated cell cycle arrest at the G
1
/S transition; however, treatment with GA resulted in a cell cycle distribution pattern identical to that of untreated cells, indicating a restoration of cell growth in HSV-1-infected cells by GA treatment. Accordingly, HSV-1 DNA synthesis was suppressed in HSV-1
+
cells treated with GA. The antiviral mechanism of GA appears to be associated with Hsp90 inactivation and cell cycle restoration, which indicates that GA exhibits broad-spectrum antiviral activity. Indeed, GA exhibited activities in vitro against other viruses, including severe acute respiratory syndrome coronavirus. Since GA inhibits HSV-1 through a cellular mechanism unique among HSV-1 agents, we consider it a new candidate agent for HSV-1.
In Vitro Activities of 3-(Halogenated Phenyl)-5-Acyloxymethyl- 2,5-Dihydrofuran-2-ones against Common and Emerging Yeasts and Molds
Authors: Buchta Vladimír , Pour Milan , Kubanová Petra , Silva Luis , Votruba Ivan , Vopršálová Marie , Schiller Radan , Fáková Helena , Špulák Marcel 
Published: February 2004

ABSTRACTThree 3-(halogenated phenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-ones were evaluated for activity against 191 strains of common and emerging yeasts andAspergillusspecies by the broth microdilution test performed according to NCCLS guidelines. The furanone derivatives displayed broad-spectrum in vitro activity against potentially pathogenic yeasts and molds, especiallyAspergillusspp. (MIC ≤ 2.0 μg/ml) and fluconazole-resistant yeast isolates, includingCandida glabrataandSaccharomyces cerevisiae. The 4-bromophenyl derivative was the most effective derivative against the majority of species tested, except for theCandida tropicalisandC. glabratastrains, which were more susceptible to the 3-chlorophenyl derivative. The 3,4-dichlorophenyl derivative possessed a lesser in vitro antifungal effect. The potential of further experiments on animal infection and clinical studies is supported by the relatively low cytotoxicity and acute toxicity of the 4-bromophenyl compound. Thus, the halogenated 3-phenyl-5-acyloxymethyl derivatives of 2,5-dihydrofuran-2-one represent a novel, promising group of compounds with significant activity against relevant opportunistic fungi that are pathogenic to humans.
Fluorescence Detection-Based Functional Assay for High-Throughput Screening for MraY
Authors: Stachyra Thérèse , Dini Christophe , Ferrari Paul , Bouhss Ahmed , van Heijenoort Jean , Mengin-Lecreulx Dominique , Blanot Didier , Biton Jacques , Le Beller Dominique 
Published: February 2004

ABSTRACT

We have developed a novel assay specific to MraY, which catalyzes the first membrane step in the biosynthesis of bacterial cell wall peptidoglycan. This was accomplished by using UDP-MurNAc-

N
ε

-dansylpentapeptide, a fluorescent derivative of the MraY nucleotide substrate, and a partially purified preparation of MraY solubilized from membranes of an
Escherichia coli
overproducing strain. Two versions of the assay were developed, one consisting of the high-pressure liquid chromatography separation of the substrate and product (dansylated lipid I) and the other, without separation and adapted to the high-throughput format, taking advantage of the different fluorescence properties of the nucleotide and lipid I in the reaction medium. The latter assay was validated with a set of natural and synthetic MraY inhibitors.
Tolerability, Pharmacokinetics, and Serum Bactericidal Activity of Intravenous Dalbavancin in Healthy Volunteers
Authors: Leighton Anton , Gottlieb Alice Bendix , Dorr Mary Beth , Jabes Daniela , Mosconi Giorgio , VanSaders Claudia , Mroszczak Edward J. , Campbell Kathleen C. M. , Kelly Ellen 
Published: February 2004

ABSTRACT

Fifty-two healthy adult male and female volunteers were enrolled in this double-blind study to determine the maximum tolerated dose, characterize the pharmacokinetics, and obtain serum bactericidal activity (SBA) data for intravenous dalbavancin. Subjects were assigned to single- or multiple-dose groups and randomized to receive dalbavancin or placebo intravenously over 30 min. Doses started at 140 mg in the single-dose group and with a 300-mg loading dose (LD), followed by six daily 30-mg maintenance doses (MDs), in the multiple-dose cohort and escalated to a 1,120-mg single dose and a 1,000-mg LD and 100-mg MD regimen. Plasma, urine, and skin blister fluid aspirate drug concentrations were measured, and pharmacokinetic parameters were determined via noncompartmental methods. SBA against methicillin-resistant
Staphylococcus aureus
(MRSA) was determined at several time points. Adverse events and changes from the baseline for laboratory data, electrocardiograms, audiologic assessments, physical examinations, and vital signs were assessed. Concentrations increased in proportion to the dose. Steady-state concentrations were achieved by day 3 with the 10:1 LD-MD regimen. The half-life averaged 181 h, and the mean volume of distribution and clearance were 9.75 liters and 0.0473 liters/h, respectively. Mean values were similar in all groups and in males and females. The portion of the dose excreted renally averaged 33.5%. Bactericidal activity was demonstrated in serum at 7 days in all subjects receiving single doses of ≥500 mg. All doses were well tolerated. Dose-limiting toxicity was not encountered. No changes in auditory or vestibular function occurred. The long half-life and maintenance of SBA against MRSA for 1 week suggest that weekly dosing may be feasible.
Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones
Authors: Zervosen Astrid , Lu Wei-Ping , Chen Zhouliang , White Ronald E. , Demuth Thomas P. , Frère Jean-Marie 
Published: February 2004

ABSTRACT

Several non-β-lactam compounds were active against various gram-positive and gram-negative bacterial strains. The MICs of arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones were lower than those of ampicillin and cefotaxime for methicillin-resistant
Staphylococcus aureus
MI339 and vancomycin-resistant
Enterococcus faecium
EF12. Several compounds were found to inhibit the cell wall synthesis of
S. aureus
and the last two steps of peptidoglycan biosynthesis catalyzed by ether-treated cells of
Escherichia coli
or cell wall membrane preparations of
Bacillus megaterium
. The effects of the arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-one derivatives on
E. coli
PBP 3 and PBP 5,
Streptococcus pneumoniae
PBP 2xS (PBP 2x from a penicillin-sensitive strain) and PBP 2xR (PBP 2x from a penicillin-resistant strain), low-affinity PBP 2a of
S. aureus
, and the
Actinomadura
sp. strain R39 and
Streptomyces
sp. strain R61
dd
-peptidases were studied. Some of the compounds exhibited inhibitory activities in the 10 to 100 μM concentration range. The inhibition of PBP 2xS by several of them appeared to be noncompetitive. The dissociation constant for the best inhibitor (
Ki
= 10 μM) was not influenced by the presence of the substrate.
The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15Ink4b in murine myeloid cells
Authors: Schmidt Martina , Bies Juraj , Tamura Tomohiko , Ozato Keiko , Wolff Linda 
Published: February 2004

AbstractCDKN2B (INK4B), which encodes the cyclin-dependent kinase inhibitor p15INK4b, is up-regulated by many cytokines found in hematopoietic environments in vivo. In human acute myeloid leukemias (AMLs), it is inactivated with high frequency. To gain insight into the regulatory pathways leading to the normal activation of p15Ink4b expression, we examined interferon β (IFNβ)–induced transcription. Using reporter gene assays in murine myeloid cells M1, we determined that a 328-bp fragment, located 117 to 443 bp upstream of the translation initiation site, was sufficient to activate transcription. Both the interferon consensus sequence-binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) and PU.1 were able to increase transcription from this region. It was determined that both ICSBP and PU.1 must bind to DNA to form a stable PU.1/ICSBP binding complex. Interestingly, introduction of the ICSBP into ICSBP-null Tot2 cells led to a significant increase in p15Ink4b RNA expression. This regulation of the Ink4b promoter is apparently myeloid specific because both ICSBP and PU.1 are myeloid commitment factors. Importantly, this provides a mechanism to explain in part the tumor suppressor activity of ICSBP, since ICSBP-deficient mice develop a chronic myelogenous leukemia (CML)–like disease and a high percentage of human AML and CML lack ICSBP transcripts.
Mechanisms associated with IL-6–induced up-regulation of Jak3 and its role in monocytic differentiation
Authors: Mangan James K. , Rane Sushil G. , Kang Anthony D. , Amanullah Arshad , Wong Brian C. , Reddy E. Premkumar 
Published: February 2004

AbstractWe report here that Janus kinase 3 (Jak3) is a primary response gene for interleukin-6 (IL-6) in macrophage differentiation, and ectopic overexpression of Jak3 accelerates monocytic differentiation of normal mouse bone marrow cells stimulated with cytokines. Furthermore, we show that incubation of normal mouse bone marrow cells with a JAK3-specific inhibitor results in profound inhibition of myeloid colony formation in response to granulocyte-macrophage colony-stimulating factor or the combination of stem cell factor, IL-3, and IL-6. In addition, mutagenesis of the Jak3 promoter has revealed that Sp1 binding sites within a -67 to -85 element and a signal transducer and activator of transcription (Stat) binding site at position -44 to -53 are critical for activation of Jak3 transcription in murine M1 myeloid leukemia cells stimulated with IL-6. Electrophoretic mobility shift assay (EMSA) analysis has demonstrated that Sp1 can bind to the -67 to -85 element and Stat3 can bind to the -44 to -53 STAT site in IL-6-stimulated M1 cells. Additionally, ectopic overexpression of Stat3 enhanced Jak3 promoter activity in M1 cells. This mechanism of activation of the murine Jak3 promoter in myeloid cells is distinct from a recently reported mechanism of activation of the human JAK3 promoter in activated T cells.