bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small Molecules VP-14637 and JNJ-2408068 Inhibit Respiratory Syncytial Virus Fusion by Similar Mechanisms
Authors: Douglas Janet L. , Panis Marites L. , Ho Edmund , Lin Kuei-Ying , Krawczyk Steve H. , Grant Deborah M. , Cai Ruby , Swaminathan Swami , Chen Xiaowu , Cihlar Tomas 
Published: May 2005

ABSTRACT

Here we present data on the mechanism of action of VP-14637 and JNJ-2408068 (formerly R-170591), two small-molecule inhibitors of respiratory syncytial virus (RSV). Both inhibitors exhibited potent antiviral activity with 50% effective concentrations (EC
50
s) of 1.4 and 2.1 nM, respectively. A similar inhibitory effect was observed in a RSV-mediated cell fusion assay (EC
50
= 5.4 and 0.9 nM, respectively). Several drug-resistant RSV variants were selected in vitro in the presence of each compound. All selected viruses exhibited significant cross-resistance to both inhibitors and contained various single amino acid substitutions in two distinct regions of the viral F protein, the heptad repeat 2 (HR2; mutations D486N, E487D, and F488Y), and the intervening domain between HR1 and HR2 (mutation K399I and T400A). Studies using [
3
H]VP-14637 revealed a specific binding of the compound to RSV-infected cells that was efficiently inhibited by JNJ-2408068 (50% inhibitory concentration = 2.9 nM) but not by the HR2-derived peptide T-118. Further analysis using a transient T7 vaccinia expression system indicated that RSV F protein is sufficient for this interaction. F proteins containing either the VP-14637 or JNJ-2408068 resistance mutations exhibited greatly reduced binding of [
3
H]VP-14637. Molecular modeling analysis suggests that both molecules may bind into a small hydrophobic cavity in the inner core of F protein, interacting simultaneously with both the HR1 and HR2 domains. Altogether, these data indicate that VP-14637 and JNJ-2408068 interfere with RSV fusion through a mechanism involving a similar interaction with the F protein.
Use of Confocal Microscopy To Analyze the Rate of Vancomycin Penetration through
Staphylococcus aureus
Biofilms
Authors: Jefferson Kimberly K. , Goldmann Donald A. , Pier Gerald B. 
Published: May 2005

ABSTRACT

When bacteria assume the biofilm mode of growth, they can tolerate levels of antimicrobial agents 10 to 1,000 times higher than the MICs of genetically equivalent planktonic bacteria. The properties of biofilms that give rise to antibiotic resistance are only partially understood. Inhibition of antibiotic penetration into the biofilm may play a role, but this has not been proven directly. In this report, penetration of the glycopeptide antibiotic vancomycin into viable
Staphylococcus aureus
biofilms was analyzed by confocal scanning laser microscopy using a fluorescently labeled derivative of the drug. We found that while vancomycin bound to free-floating bacteria in water within 5 min, it took more than 1 h to bind to cells within the deepest layers of a biofilm. These results indicate that the antibiotic is transported through the depth of the biofilm but that the rate is significantly reduced with respect to its transport through flowing water. This suggests that, whereas planktonic bacteria were rapidly exposed to a full bolus of vancomycin, the bacteria in the deeper layers of the biofilm were exposed to a gradually increasing dose of the drug due to its reduced rate of penetration. This gradual exposure may allow the biofilm bacteria to undergo stress-induced metabolic or transcriptional changes that increase resistance to the antibiotic. We also investigated the role of poly-
N
-acetylglucosamine, an important component of the
S. aureus
biofilm matrix, and found that its production was not involved in the observed decrease in the rate of vancomycin penetration.
Mechanisms of Antibacterial Action of Three Monoterpenes
Authors: Trombetta Domenico , Castelli Francesco , Sarpietro Maria Grazia , Venuti Vincenza , Cristani Mariateresa , Daniele Claudia , Saija Antonella , Mazzanti Gabriela , Bisignano Giuseppe 
Published: May 2005

ABSTRACT

In the present paper, we report the antimicrobial efficacy of three monoterpenes [linalyl acetate, (+)menthol, and thymol] against the gram-positive bacterium
Staphylococcus aureus
and the gram-negative bacterium
Escherichia coli
. For a better understanding of their mechanisms of action, the capability of these three monoterpenes to damage biomembranes was evaluated by monitoring the release, following exposure to the compounds under study, of the water-soluble fluorescent marker carboxyfluorescein from unilamellar vesicles with different lipidic compositions (phosphatidylcholine, phosphatidylcholine/phosphatidylserine [9:1], phosphatidylcholine/stearylamine [9:1], and phosphatidylglycerol/cardiolipin [9:1]). Furthermore, the interaction of the terpenes tested with dimyristoylphosphatidylcholine multilamellar vesicles as model membranes was monitored by means of differential scanning calorimetry. Finally, the results were related to the relative lipophilicity and water solubility of the compounds examined. Taken together, our findings lead us to speculate that the antimicrobial effect of (+)menthol, thymol, and linalyl acetate may result, at least partially, from a perturbation of the lipid fraction of microorganism plasma membrane, resulting in alterations of membrane permeability and in leakage of intracellular materials. Besides being related to physicochemical characteristics of the drugs (such as lipophilicity and water solubility), this effect seems to be dependent on lipid composition and net surface charge of microbial membranes. Furthermore, the drugs might cross the cell membranes, penetrating into the interior of the cell and interacting with intracellular sites critical for antibacterial activity.
Novel Ser79Leu and Ser81Ile Substitutions in the Quinolone Resistance-Determining Regions of ParC Topoisomerase IV and GyrA DNA Gyrase Subunits from Recent Fluoroquinolone-Resistant
Streptococcus pneumoniae
Clinical Isolates
Authors: Korzheva Nataliya , Davies Todd A. , Goldschmidt Raul 
Published: May 2005

ABSTRACT

Resistance of
Streptococcus pneumoniae
to fluoroquinolones is caused predominantly by amino acid substitutions at positions Ser79 of ParC and Ser81 of GyrA to either Phe or Tyr encoded in the quinolone resistance-determining regions of the
parC
topoisomerase IV and
gyrA
DNA gyrase genes. Analysis of highly resistant clinical isolates identified novel second-step substitutions, Ser79Leu (ParC) and Ser81Ile (GyrA). To determine contributions of these new mutations to fluoroquinolone resistance either alone or in combination with other Ser79/81 alleles, the substitutions Ser79Leu/Phe/Tyr in ParC and Ser81Ile/Phe/Tyr in GyrA were introduced into the R6 background, resulting in 15 isogenic strains. Their level of fluoroquinolone resistance was determined by susceptibility testing for ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin, garenoxacin, and norfloxacin. Leu79 and Ile81 alone as well as 79/81Phe/Tyr substitutions did not contribute significantly to resistance, with fluoroquinolone MICs increasing two- to fourfold compared to wild type for all agents tested. Fluoroquinolone MICs for double transformants ParC Ser79Phe/Tyr/Leu-GyrA Ser81Phe/Tyr were uniformly increased by 8- to 64-fold regardless of pairs of amino acid substitutions. However, combinations including Ile81 conferred two- to fourfold-higher levels of resistance than did combinations including any other Ser81 GyrA substitution, thus demonstrating the differential effects of diverse amino acid substitutions at particular hotspots on fluoroquinolone MICs.
In Vitro Activity of Telithromycin against Macrolide-Susceptible and Macrolide-Resistant Pharyngeal Isolates of Group A Streptococci in the United States
Authors: Green Michael , Allen Coburn , Bradley John , Dashefsky Barry , Gilsdorf Janet R. , Marcon Mario J. , Schutze Gordon E. , Smith Clay , Walter Emmanuel , Martin Judith M. , Edwards Kathryn A. , Barbadora Karen A. , Rumbaugh Renee M. , Wald Ellen R. 
Published: May 2005

ABSTRACT
In vitro susceptibility testing of 2,797 group A streptococcus (GAS) isolates demonstrated that telithromycin was fully active against all macrolide-susceptible strains and among 80 of 115 macrolide-resistant GAS expressing the M phenotype. Telithromycin resistance was identified in 2 of 45 strains expressing the inducible macrolide-lincosamide-streptogramin B phenotype and four of nine isolates expressing the constitutive macrolide-lincosamide-streptogramin B resistance phenotype.
DNA in Antibiotic Preparations: Absence of Intact Resistance Genes
Authors: Woegerbauer Markus , Lagler Heimo , Graninger Wolfgang , Burgmann Heinz 
Published: May 2005

ABSTRACT

Fragments of
erm
(E2),
otrA
, and
aph
(6) shorter than 400 bp and producer strain-specific rRNA genes were amplified from various antibiotics. The amount of genetic material and the sizes of amplicons recovered from murine feces after oral administration of a β-lactamase-encoding plasmid indicated substantial DNA degradation in the mammalian gastrointestinal tract. These observations imply that antibiotics are no major source for horizontal resistance gene transfer in clinical settings.
In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria
Authors: Yoon Eun Jeong , Jo Yeong Woo , Choi Sung Hak , Lee Tae Ho , Rhee Jae Keol , Yoo Moohi , Shim Mi Ja , Choi Eung Chil 
Published: May 2005

ABSTRACT

In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant
Staphylococcus aureus
, vancomycin-resistant enterococci, and penicillin-resistant
Streptococcus pneumoniae
. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.
Biosynthesized Tea Polyphenols Inactivate
Chlamydia trachomatis
In Vitro
Authors: Yamazaki Tsutomu , Kishimoto Toshio , Shiga Sadashi , Sato Kozue , Hagiwara Toshikatsu , Inoue Miyuki , Sasaki Nozomu , Ouchi Kazunobu , Hara Yukihiko 
Published: May 2005

ABSTRACT

Biosynthesized tea polyphenols showed antichlamydial activity against
Chlamydia trachomatis
D/UW-3/Cx and L
2
/434/Bu using cell culture. The most active compounds were (−)-epigallocatechin gallate and (−)-epicatechin gallate, followed by (−)-epicatechin (EC). (+)-Epicatechin and (−)-epigallocatechin were intermediate. EC was the least toxic. These results warrant evaluation of tea polyphenols as topical antichlamydial agents.
Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid
Authors: Capparelli Edmund V. , Letendre Scott L. , Ellis Ronald J. , Patel Parul , Holland Diane , McCutchan J. Allen 
Published: May 2005

ABSTRACT
The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.
In Vitro Inhibitory Effects of Hinokitiol on Proliferation of
Chlamydia trachomatis
Authors: Yamano Hiroaki , Yamazaki Tsutomu , Sato Kozue , Shiga Sadashi , Hagiwara Toshikatsu , Ouchi Kazunobu , Kishimoto Toshio 
Published: May 2005

ABSTRACT

The inhibitory effects of hinokitiol (β-thujaplicin) on
Chlamydia trachomatis
D/UW-3/Cx were shown by MIC, minimum lethal concentration (MLC), and preinoculation minimal microbicidal concentration assays using HeLa 229 cells. The MIC and the MLC were both 32 μg/ml. Further evaluation of hinokitiol as a topical agent against
C. trachomatis
is warranted.
Detection of
qnr
in Clinical Isolates of
Escherichia coli
from Korea
Authors: Jeong Jin-Yong , Yoon Hyun Jung , Kim Eun Sil , Lee Yoola , Choi Sang-Ho , Kim Nam Joong , Woo Jun Hee , Kim Yang Soo 
Published: May 2005

ABSTRACT

qnr
was detected in 2 of 260
Escherichia coli
clinical isolates collected from a Korean hospital during the period 2001 to 2003. The two strains were not clonally related.
qnr
was located in In4 family class 1 integrons of original structure, downstream of orf513 and upstream from another resistance gene (
dfrA3b
) and a gene of unknown function (orf105). Transfer of the
qnr
determinant by conjugation could be detected from only one strain.
Effect of CYP3A1(23) Induction on Clarithromycin Pharmacokinetics in Rats with Diabetes Mellitus
Authors: Kim Yu C. , Lee Joo H. , Kim So H. , Lee Myung G. 
Published: May 2005

ABSTRACT
After intravenous and oral administration of clarithromycin at a dose of 20 mg/kg of body weight to rats with diabetes mellitus induced by alloxan (DMIA) and diabetes mellitus induced by streptozotocin (DMIS), the area under the curve values were significantly smaller than those of respective control rats. The in vitro intrinsic clearance values for the disappearance of clarithromycin were significantly faster in both rats with DMIA and rats with DMIS than in control rats. The above data suggested that metabolism of clarithromycin increased in both types of diabetic rat due to an increase in the expression and mRNA level of CYP3A1(23) in the rats.
In Vitro and Intracellular Activities of LBM415 (NVP PDF-713) against
Legionella pneumophila
Authors: Edelstein Paul H. , Hu Baofeng , Edelstein Martha A. C. 
Published: May 2005

ABSTRACT

LBM415 activity against extracellular and intracellular
Legionella pneumophila
was studied. The LBM415 MIC
50
for 20
Legionella
sp. strains was 4 μg/ml, versus 0.06, 0.25, and ≤ 0.03 μg/ml for azithromycin, erythromycin, and levofloxacin, respectively. LBM415 (0.5 and 16 μg/ml) reversibly prevented intracellular growth of two
L. pneumophila
strains and was less active than erythromycin.
Targeted Gene Disruption of the 14-α Sterol Demethylase (
cyp51A
) in
Aspergillus fumigatus
and Its Role in Azole Drug Susceptibility
Authors: Mellado E. , Garcia-Effron G. , Buitrago M. J. , Alcazar-Fuoli L. , Cuenca-Estrella M. , Rodriguez-Tudela J. L. 
Published: May 2005

ABSTRACT

The role of
Aspergillus fumigatus
14α-sterol demethylase (Cyp51A) in azole drug susceptibility was assessed. Targeted disruption of
cyp51A
in azole-susceptible and -resistant strains decreased MICs from 2- to 40-fold. The
cyp51A
mutants were morphologically indistinguishable from the wild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice.
In Vitro Activities of Amphotericin B and Voriconazole against Aleurioconidia from
Aspergillus terreus
Authors: Lass-Flörl Cornelia , Rief Alexandra , Leitner Sandra , Speth Cornelia , Würzner Reinhard , Dierich Manfred P. 
Published: May 2005

ABSTRACT

This study used aleurioconidia as inoculum and compared the MICs of amphotericin B and voriconazole to those obtained for conidia of 31
Aspergillus terreus
strains. For conidia and aleurioconidia, the MIC at which 90% of strains were inhibited was 2.5 μg/ml and 5 μg/ml with amphotericin B and 1 μg/ml and 2 μg/ml with voriconazole.
Comparative In Vitro Activities of Investigational Peptide Deformylase Inhibitor NVP LBM-415 and Other Agents against Human Mycoplasmas and Ureaplasmas
Authors: Waites Ken B. , Reddy Nipun B. , Crabb Donna M. , Duffy Lynn B. 
Published: May 2005

ABSTRACTPeptide deformylase inhibitor LBM-415 and seven other drugs were tested againstMycoplasma pneumoniae(100 isolates),Mycoplasma hominis(20 isolates),Mycoplasma fermentans(10 isolates), andUreaplasmaspecies (50 isolates). LBM-415 was active againstM. pneumoniae(MICs, ≤0.008 μg/ml). It showed no activity againstM. hominisandM. fermentansand modest activity againstUreaplasmaspp.
Caspofungin in Combination with Amphotericin B against
Candida glabrata
Authors: Barchiesi Francesco , Spreghini Elisabetta , Fothergill Annette W. , Arzeni Daniela , Greganti Gianfranco , Giannini Daniele , Rinaldi Michael G. , Scalise Giorgio 
Published: May 2005

ABSTRACT

The effects of caspofungin combined with amphotericin B were investigated with
Candida glabrata
. Although in vitro experiments showed an indifferent interaction, the combination regimen was the only therapeutic approach yielding organ sterilization in a murine candidemia model.
Utilization of Target-Specific, Hypersensitive Strains of
Saccharomyces cerevisiae
To Determine the Mode of Action of Antifungal Compounds
Authors: Buurman Ed T. , Andrews Beth , Blodgett April E. , Chavda Jini S. , Schnell Norbert F. 
Published: May 2005

ABSTRACT

Target-specific hypersusceptible strains of
Saccharomyces cerevisiae
were used to screen antifungal compounds. Two novel Erg7p inhibitors were identified, providing proof of principle of the approach taken. However, observed hypersensitivities to antifungals acting via other targets imply that use of this tool to identify the mode of action requires significant deconvolution.
Chromosome-Borne Class A BOR-1 β
-
Lactamase of
Bordetella bronchiseptica
and
Bordetella parapertussis
Authors: Lartigue Marie-Frédérique , Poirel Laurent , Fortineau Nicolas , Nordmann Patrice 
Published: May 2005

ABSTRACT

A narrow-spectrum clavulanic acid-inhibited class A β-lactamase, BOR-1, was identified in a
Bordetella bronchiseptica
clinical isolate. It shared 45% amino acid identity with L-2 from
Stenotrophomonas maltophilia
. An identical β-lactamase gene was found in
B. bronchiseptica
and
Bordetella parapertussis
reference strains that may contribute only in part to their resistance phenotype.
Identification of CTX-M-14 β-Lactamase in a
Salmonella enterica
Serovar Enteritidis Isolate from Japan
Authors: Izumiya Hidemasa , Mori Kadumi , Higashide Masato , Tamura Kazumichi , Takai Nobuko , Hirose Kenji , Terajima Jun , Watanabe Haruo 
Published: May 2005

ABSTRACT

We analyzed the resistance to cefotaxime of a
Salmonella enterica
serovar Enteritidis isolate from a stool culture of a 4-year-old boy. It produced a β-lactamase CTX-M-14, encoded by two related R plasmids. The region surrounding the
bla
CTX-M-14
gene had an original mosaic structure containing insertion sequences (IS
26
and IS
903D
).
Markers of apoptosis in stage IB squamous cervical carcinoma
Authors: Van de Putte G , Holm R , Lie A K , Baekelandt M , Kristensen G B 
Published: May 2005

Aims:To examine the prognostic relevance of the expression of the Bcl-2, Bcl-xL, and Bax proteins in stage IB squamous cervical carcinoma (SCC).Methods:In total, 220 patients who underwent radical hysterectomy and bilateral lymphadenectomy at the Norwegian Radium Hospital for stage IB SCC between 1987 and 1993 were studied. Immunohistochemistry using monoclonal antibodies against Bcl-2, Bcl-xL, and Bax was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls.Results:Cytoplasmic expression of Bcl-2, Bcl-xL, and Bax was low (< 5% positive cells) in 159 of 220 (73%), 193 of 220 (87%), and 39 of 220 (18%) tumours, respectively, and high (⩾ 5% positive cells) in 61 of 220 (27%), 27 of 220 (13%), and 181 of 220 (82%) tumours, respectively. In univariate analysis, all classic clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival.Conclusion:Bcl-2, Bcl-xL, and Bax were not independently associated with prognosis in stage IB SCC.
The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumours is site and phenotype associated
Authors: Penzel R , Aulmann S , Moock M , Schwarzbach M , Rieker R J , Mechtersheimer G 
Published: May 2005

Aims:To assess the relation between KIT and PDGFRA mutations and the site of origin, histological phenotype, and pathomorphologically determined risk assessment in gastrointestinal stromal tumours (GISTs).Methods:A series of 83 clinicopathologically characterised GISTs from 79 patients was analysed for KIT and PDGFRA mutations by polymerase chain reaction amplification, single strand conformation polymorphism analysis, and direct DNA sequencing.Results:KIT or PDGFRA mutations were found in 57 and 11 GISTs, respectively. Most KIT mutations involved exon 11 (46 cases), followed by exon 9 (10 cases). The PDGFRA mutations mostly affected exon 18 (eight cases), followed by exon 12 (three cases). There was a significant association between KIT exon 9 mutations and an intestinal origin of GISTs, and between PDGFRA mutations and gastric origin of the tumours. In addition, the presence of PDGFRA mutations was significantly associated with epithelioid/mixed histology, as was the absence of identified receptor tyrosine kinase mutations. Vice versa, KIT exon 11 mutations were almost exclusively found in spindle cell GISTs. Furthermore, the presence of any KIT and PDGFRA mutations and the presence of KIT mutations alone were significantly associated with high risk/malignant GISTs.Conclusions:The location of KIT and PDGFRA mutations in GISTs is associated with the site of origin and histological phenotype. Genotyping of GISTs may be a helpful additional parameter in determining the biological profile of these tumours.
Gastric ciliated metaplasia. A study of 3406 gastrectomy specimens from dwellers of the Atlantic and the Pacific basins
Authors: Rubio C A , Nesi G , Zampi G C , de Ruiz P A , Jessurun J , Jónasson J , Hojman R , Kogan Z , Antonioli D , Miller M L , Hirota T , Itabashi T , Mandai K , Kitagawa T , Sugano H , Kato Y , King A , Pisano R , Owen D 
Published: May 2005

Background:Ciliated cells in gastrectomies from patients dwelling in the Pacific and Atlantic basins have been reported previously.Aim:To compare all the results in an attempt to explain the findings.Methods:Sections from 3406 gastrectomies were reviewed: 1966 and 1440 from the Atlantic and Pacific basins, respectively. Ciliated cells and intestinal metaplasia (IM) were recorded; IM was classified into focal or extensive IM. The total number of sections/gastrectomy was noted.Results:In the Atlantic basin, 5% of specimens had ciliated metaplasia (CM); it was more frequent in intestinal carcinoma (IC; 9%) than diffuse carcinoma (DC; 3%) or miscellaneous gastric diseases (MGD; 3%). In the Pacific basin, the frequency of specimens with CM was 29%: it was more frequent in IC (43%) than in DC (16%) or MGD (10%). The difference between the frequency of CM in specimens with IC or with DC/MGD in the Atlantic and the Pacific basins was significant (p ⩽ 0.05). The presence of CM was influenced by age and the extent of IM in both basins, but not by sex or the number of sections investigated.Conclusions:CM—apparently an independent microscopic marker—was significantly higher in the Pacific than in the Atlantic basin. Environmental carcinogens involved in the evolution of IM and IC seem to be implicated in gastric ciliogenesis. Carcinogens that differ in nature and/or in strength in both basins might activate the latent natural genes encoding ciliated processes in gastric cells in patients subsequently developing gastric carcinoma, more notably of intestinal type.