bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salmonella enterica
Serovar Typhimurium
bla
PER-1
-Carrying Plasmid pSTI1 Encodes an Extended-Spectrum Aminoglycoside 6′-
N
-Acetyltransferase of Type Ib
Authors: Casin Isabelle , Hanau-Berçot Beatrice , Podglajen Isabelle , Vahaboglu Haluk , Collatz Ekkehard 
Published: January 2003

ABSTRACT

We have studied the aminoglycoside resistance gene, which confers high levels of resistance to both amikacin and gentamicin, that is carried by plasmid pSTI1 in the PER-1 β-lactamase-producing strain of
Salmonella enterica
serovar Typhimurium previously isolated in Turkey. This gene, called
aac(6
′

)-Ib
11

, was found in a class 1 integron and codes for a protein of 188 amino acids, a fusion product between the N-terminal moiety (8 amino acids) of the signal peptide of the β-lactamase OXA-1 and the acetyltransferase. The gene lacked a plausible Shine-Dalgarno (SD) sequence and was located 45 nucleotides downstream from a small open reading frame, ORF-18, with a coding capacity of 18 amino acids and a properly spaced SD sequence likely to direct the initiation of
aac(6
′

)-Ib
11

translation. AAC(6′)-Ib
11
had Leu118 and Ser119 as opposed to Gln and Leu or Gln and Ser, respectively, which were observed in all previously described enzymes of this type. We have evaluated the effect of Leu or Gln at position 118 by site-directed mutagenesis of
aac(6
′

)-Ib
11

and two other acetyltransferase gene variants,
aac(6
′

)-Ib
7

and

-Ib
8

, which naturally encode Gln118. Our results show that the combination of Leu118 and Ser119 confers an extended-spectrum aminoglycoside resistance, with the MICs of all aminoglycosides in clinical use, including gentamicin, being two to eight times higher for strains with Leu118 and Ser119 than for those with Gln118 and Ser119.
Efflux Pump Lde Is Associated with Fluoroquinolone Resistance in
Listeria monocytogenes
Authors: Godreuil Sylvain , Galimand Marc , Gerbaud Guy , Jacquet Christine , Courvalin Patrice 
Published: January 2003

ABSTRACT

Five
Listeria monocytogenes
isolates (CLIP 21369, CLIP 73298, CLIP 74811, CLIP 75679, and CLIP 79372) were found to be resistant to fluoroquinolones during the screening for antibiotic resistance of 488
L. monocytogenes
isolates from human cases of listeriosis in France. On the basis of a fourfold or greater decrease in the ciprofloxacin MIC in the presence of reserpine, fluoroquinolone resistance was attributed to active efflux of the drugs. The
lde
gene (
Listeria
drug efflux; formerly
lmo2741
) encodes a 12-transmembrane-segment putative efflux pump belonging to the major facilitator superfamily of secondary transporters that displayed 44% identity with PmrA from
Streptococcus pneumoniae
. Insertional inactivation of the
lde
gene in CLIP 21369 indicated that the corresponding protein was responsible for fluoroquinolone resistance and was involved in the level of susceptibility to dyes such as ethidium bromide and acridine orange.
Genetics of Mefloquine Resistance in the Rodent Malaria Parasite
Plasmodium chabaudi
Authors: Cravo Pedro V. L. , Carlton Jane M.-R. , Hunt Paul , Bisoni Laura , Padua Rose Ann , Walliker David 
Published: January 2003

ABSTRACT

The genetic determinants of resistance to mefloquine in malaria parasites are unclear. Some studies have implied that amplification of, or mutations in, the multidrug resistance gene
pfmdr1
in
Plasmodium falciparum
may be involved. Using the rodent malaria model
Plasmodium chabaudi
, we investigated the role of the orthologue of this gene,
pcmdr1
, in a stable mefloquine-resistant mutant, AS(15MF/3), selected from a sensitive clone.
pcmdr1
exists as a single copy gene on chromosome 12 of the sensitive clone. In AS(15MF/3), the gene was found to have undergone duplication, with one copy translocating to chromosome 4. mRNA levels of
pcmdr1
were higher in the mutant than in the parent sensitive clone. A partial genetic map of the translocation showed that other genes in addition to
pcmdr1
had been cotranslocated. The sequences of both copies of
pcmdr1
of AS(15MF/3) were identical to that of the parent sensitive clone. A cross was made between AS(15MF/3) and an unrelated mefloquine-sensitive clone, AJ. Phenotypic and molecular analysis of progeny clones showed that duplication and overexpression of the
pcmdr1
gene was an important determinant of resistance. However, not all mefloquine-resistant progeny contained the duplicated gene, showing that at least one other gene was involved in resistance.
Phenothiazines and Thioxanthenes Inhibit Multidrug Efflux Pump Activity in
Staphylococcus aureus
Authors: Kaatz Glenn W. , Moudgal Varsha V. , Seo Susan M. , Kristiansen Jette E. 
Published: January 2003

ABSTRACT

Efflux-related multidrug resistance (MDR) is a significant means by which bacteria can evade the effects of selected antimicrobial agents. Genome sequencing data suggest that
Staphylococcus aureus
may possess numerous chromosomally encoded MDR efflux pumps, most of which have not been characterized. Inhibition of these pumps, which may restore clinically relevant activity of antimicrobial agents that are substrates for them, may be an effective alternative to the search for new antimicrobial agents that are not substrates. The inhibitory effects of selected phenothiazines and two geometric stereoisomers of the thioxanthene flupentixol were studied using strains of
S. aureus
possessing unique efflux-related MDR phenotypes. These compounds had some intrinsic antimicrobial activity and, when combined with common MDR efflux pump substrates, resulted in additive or synergistic interactions. For
S. aureus
SA-1199B, which overexpresses the NorA MDR efflux pump, and for two additional strains of
S. aureus
having non-NorA-mediated MDR phenotypes, the 50% inhibitory concentration (IC
50
) for ethidium efflux for all tested compounds was between 4 and 15% of their respective MICs. Transport of other substrates was less susceptible to inhibition; the prochlorperazine IC
50
for acriflavine and pyronin Y efflux by SA-1199B was more than 60% of its MIC. Prochlorperazine and
trans
(E)-flupentixol were found to reduce the proton motive force (PMF) of
S. aureus
by way of a reduction in the transmembrane potential. We conclude that the mechanism by which phenothiazines and thioxanthenes inhibit efflux by PMF-dependent pumps is multifactorial and, because of the unbalanced effect of these compounds on the MICs and the efflux of different substrates, may involve an interaction with the pump itself and, to a lesser extent, a reduction in the transmembrane potential.
Molecular Epidemiology of the SRL Pathogenicity Island
Authors: Turner Sally A. , Luck Shelley N. , Sakellaris Harry , Rajakumar Kumar , Adler Ben 
Published: January 2003

ABSTRACT

The Shigella resistance locus (SRL), which is carried on the SRL pathogenicity island (PAI) in
Shigella flexneri
2a YSH6000, mediates resistance to the antibiotics streptomycin, ampicillin, chloramphenicol, and tetracycline. In the present study, we investigated the distribution and structural variation of the SRL and the SRL PAI in 71
Shigella
isolates and 28 other enteric pathogens by PCR and Southern analysis. The SRL and SRL-related loci, although absent from the other enteric pathogens evaluated in this study, were found to be present in a number of
Shigella
isolates. SRL PAI markers were also present in the majority of strains carrying the SRL and SRL-related loci. PCR linkage studies with six of these strains demonstrated that the SRL is carried on elements similar in structure and organization to the YSH6000 SRL PAI, consistent with the hypothesis that the SRL PAI may be involved in the spread of multiple-antibiotic resistance in these strains.
Fosmidomycin, a Novel Chemotherapeutic Agent for Malaria
Authors: Lell Bertrand , Ruangweerayut Ronnatrai , Wiesner Jochen , Missinou Michel Anoumou , Schindler Andreas , Baranek Thomas , Hintz Martin , Hutchinson David , Jomaa Hassan , Kremsner Peter Gottfried 
Published: January 2003

ABSTRACT

In previous studies, fosmidomycin has been shown to possess activity against
Plasmodium falciparum
in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy-
d
-xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, uncontrolled trial, the efficacy and safety of fosmidomycin, in an oral dose of 1,200 mg every 8 h for 7 days, were evaluated in the treatment of acute uncomplicated
Plasmodium falciparum
malaria in 20 adult subjects in Gabon and Thailand. Clinical assessments were performed and thick blood smears were evaluated every 8 h until parasite clearance and resolution of symptoms were achieved; assessments continued at weekly intervals thereafter for the duration of the 28-day followup period. All subjects were clinically and parasitologically cured on day 7 (primary end point). Parasite and fever clearance were rapid, with means of 44 and 41 h, respectively. On day 28, seven out of nine subjects (78%) were cured in Gabon and two out of nine subjects (22%) were cured in Thailand. The drug was well tolerated, although mild gastrointestinal side effects were recorded for five subjects. Analysis of hematological and biochemical parameters showed no clinically significant changes throughout the study. Fosmidomycin is an effective and safe antimalarial drug, although its use as a single agent is restricted by the occurrence of recrudescent infections. However, its role in combination therapy should be explored.
Influence of Macrolide Susceptibility on Efficacies of Clarithromycin and Azithromycin against
Streptococcus pneumoniae
in a Murine Lung Infection Model
Authors: Hoffman Holly L. , Klepser Michael E. , Ernst Erika J. , Petzold C. Rosemarie , Sa'adah Loai Mohammed , Doern Gary V. 
Published: January 2003

ABSTRACT

We evaluated the activities of clarithromycin and azithromycin against 19 isolates of
Streptococcus pneumoniae
using a neutropenic lung infection model. The isolates included five susceptible isolates (clarithromycin and azithromycin MICs, ≤0.12 μg/ml), nine isolates exhibiting low-level,
mefA
-mediated resistance (clarithromycin and azithromycin MICs, 0.5 to 32 μg/ml), and five isolates expressing high-level,
ermB
-mediated macrolide resistance (clarithromycin and azithromycin MICs, ≥64 μg/ml). Infected mice were administered either saline (control), clarithromycin (4, 40, or 200 mg/kg of body weight twice daily or 200 mg/kg once daily), or azithromycin (4, 40, or 200 mg/kg once daily or 40 mg/kg twice daily) by oral gavage for 72 h. Mortality was assessed at regular intervals for 10 days, and survival in each group was compared to that of untreated controls. Animals infected with susceptible isolates demonstrated significant improvement in survival compared to the controls following treatment with either agent at doses of ≥40 mg/kg. In contrast, none of the regimens improved the survival of animals infected with isolates exhibiting high-level macrolide resistance. Among mice infected with strains expressing low-level resistance, significant improvement in survival compared to the controls was noted among isolates treated with clarithromycin at 40 (seven of nine isolates) and 200 (nine of nine isolates) mg/kg twice a day and with azithromycin at 40 (one of nine isolates) and 200 (three of nine isolates) mg/kg once a day. Animals infected with isolates of
S. pneumoniae
exhibiting low-level,
mefA
-mediated macrolide resistance responded to treatment with clarithromycin at rates similar to those observed among mice infected with fully susceptible isolates.
Lamivudine Can Exert a Modest Antiviral Effect against Human Immunodeficiency Virus Type 1 Containing the M184V Mutation
Authors: Quan Yudong , Brenner Bluma G. , Oliveira Maureen , Wainberg Mark A. 
Published: January 2003

ABSTRACTThe M184V mutation in human immunodeficiency virus (HIV) reverse transcriptase is associated with high-level resistance to both (−)2′,3′-dideoxy-3′-thiacytidine (3TC) and (−)2′,3′-dideoxy-5-fluoro-3′-thiacytidine as well as low-level resistance to 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, and abacavir. This mutation is also associated with diminished HIV replicative fitness as well as several functional changes in enzyme activity, including diminutions in polymerase processivity, pyrophosphorylysis, and nucleotide primer unblocking. Despite the fact that M184V encodes up to 1,000-fold resistance to 3TC, we asked whether this drug might still display some antiviral effect in regard to viruses containing this mutation. Cell-free assays revealed that high concentrations of 3TC triphosphate (i.e., >100 μM) could affect chain termination and/or inhibit purified reverse transcriptase containing the M184V substitution. This effect became more pronounced with elongation of reverse transcriptase products. In newly infected cells (i.e., peripheral blood mononuclear cells), we found that the amount of full-length reverse transcriptase product was diminished in the presence of 2 to 10 μM 3TC, although no decrease in the first product of the reverse transcriptase reaction, i.e., minus strong-stop DNA, was observed. In the presence of two other HIV inhibitors, e.g., nevirapine and indinavir, 3TC exerted additive effects in tissue culture at concentrations only marginally higher than the 50% inhibitory concentration (IC50). Reverse transcriptases cloned from clinical isolates harboring M184V in the context of multidrug resistance had similar IC50values for 3TC triphosphate compared to reverse transcriptase containing only the M184V mutation. These results suggest that viruses containing M184V can retain a higher degree of sensitivity to 3TC than previously assumed.
Emergence inKlebsiella pneumoniaeof a Chromosome-Encoded SHV β-Lactamase That Compromises the Efficacy of Imipenem
Authors: Poirel Laurent , Héritier Claire , Podglajen Isabelle , Sougakoff Wladimir , Gutmann Laurent , Nordmann Patrice 
Published: January 2003

ABSTRACTAKlebsiella pneumoniaeisolate was identified that had reduced susceptibility to several expanded-spectrum cephalosporins and imipenem. That isolate produced a chromosome-encoded SHV-type β-lactamase, SHV-38, that had an alanine to valine substitution in position Ambler 146 compared to β-lactamase SHV-1. The kinetic parameters for purified β-lactamases SHV-38 and SHV-1 showed that the hydrolytic spectrum of SHV-38 included only ceftazidime and imipenem. This report is the first example of an SHV-type β-lactamase capable of hydrolyzing imipenem.
Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors
Authors: Watkins Terri , Resch Wolfgang , Irlbeck David , Swanstrom Ronald 
Published: January 2003

ABSTRACTProtease inhibitors represent some of the most potent agents available for therapeutic strategies designed to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Under certain circumstances the virus develops resistance to the inhibitor, thereby negating the benefits of this therapy. We have carried out selections for high-level resistance to each of three protease inhibitors (indinavir, ritonavir, and saquinavir) in cell culture. Mutations accumulated over most of the course of the increasing selective pressure. There was significant overlap in the identity of the mutations selected with the different inhibitors, and this gave rise to high levels of cross-resistance. Virus particles from the resistant variants all showed defects in processing at the NC/p1 protease cleavage site in Gag. Selections with pairs of inhibitors yielded similar patterns of resistance mutations. A virus that could replicate at near-toxic levels of the three protease inhibitors combined was selected. Theprosequence of this virus was similar to that of the viruses that had been selected for high-level resistance to each of the drugs singly. Finally, a molecular clone carrying the eight most common resistance mutations seen in these selections was characterized. The sequence of this virus was relatively stable during selection for revertants in spite of displaying poor processing at the NC/p1 site and having significantly reduced fitness. These results reveal patterns of drug resistance that extend to near the limits of attainable selective pressure with these inhibitors and confirm the patterns of cross-resistance for these three inhibitors and the attenuation of virion protein processing and fitness that accompanies high-level resistance.
In Vitro and In Vivo Pharmacokinetics-Pharmacodynamics of GV143253A, a Novel Trinem
Authors: Ferrari Livia , Iavarone Laura , Braggio Simone , Di Modugno Enza 
Published: January 2003

ABSTRACTThe aim of the present study was to characterize the pharmacokinetic-pharmacodynamic relationship of GV143253A, a novel trinem anti-methicillin-resistantStaphylococcus aureus(MRSA) agent active against gram-positive cocci, including multidrug-resistant clinical isolates. An in vitro pharmacodynamic study with methicillin-susceptibleS. aureus(MSSA) and MRSA has shown that the duration of exposure to GV143253A rather than its concentration is the major determinant of the extent of bacterial killing. The in vitro findings were confirmed by use of a neutropenic murine model of thigh infection caused by MSSA ATCC 25923. From the dose-response curves, the static doses extrapolated for three different dosing intervals showed that more frequent dosing of GV143253A was more effective than less frequent dosing. A pharmacokinetic-pharmacodynamic analysis demonstrated that only the time during which the drug concentration exceeded the MIC (t>MIC) correlated with in vivo GV143253A activity. The value oft>MIC required to achieve a bacteriostatic effect in a thigh infection of neutropenic animals was 20% (95% confidence interval [CI], 18 to 22%) of the dosing interval. This result is similar to those reported in the literature for carbapenems and for GV104326A, another novel trinem compound. In addition, in order to compare the therapeutic efficacy of GV143253A to that of vancomycin in a thigh infection caused by MRSA in immunocompetent mice, suitable dosing regimens were designed on the basis of previous pharmacokinetic-pharmacodynamic findings for GV143253A and on the human pharmacokinetic profile of the glycopeptide. Although the pharmacokinetic profiles of the two agents were completely different, GV143253A showed good efficacy comparable to that of vancomycin, reducing by 4 log units the bacterial counts in the thighs of treated mice relative to untreated infected animals after 48 h of therapy. The results suggest that if the time of exposure to the pathogen above the MIC is at least 30% of the dosing interval, GV143253A could have a role in the clinical treatment of infections caused by MRSA, which is difficult to eradicate with current antibiotics.
Interferons, Interferon Inducers, and Interferon-Ribavirin in Treatment of Flavivirus-Induced Encephalitis in Mice
Authors: Leyssen Pieter , Drosten Christian , Paning Marcus , Charlier Nathalie , Paeshuyse Jan , De Clercq Erik , Neyts Johan 
Published: January 2003

ABSTRACT
We evaluated the prophylactic and therapeutic efficacy of interferon α-2b, pegylated interferon α-2b, poly(I · C), and Ampligen against Modoc virus encephalitis in an animal model for flavivirus infections. All compounds significantly delayed virus-induced morbidity (paralysis) and mortality (due to progressive encephalitis). Viral load (as measured on day 7 postinfection) was significantly reduced by 80 to 100% in the serum, brain, and spleen in mice that had been treated with either interferon α-2b, pegylated interferon α-2b, poly(I · C), or Ampligen. We also studied whether a combination of interferon α-2b and ribavirin (presently the standard therapy for the treatment of infections with hepatitis C virus) would be more effective than treatment with interferon alone. However, ribavirin did not enhance the inhibitory effect of interferon therapy in this animal model for flavivirus infections.
Rapid In Vivo Screening of Experimental Drugs for Tuberculosis Using Gamma Interferon Gene-Disrupted Mice
Authors: Lenaerts Anne J. M. , Gruppo Veronica , Brooks Jason V. , Orme Ian M. 
Published: January 2003

ABSTRACT

We have developed a rapid new in vivo method for screening experimental drugs for their activity against
Mycobacterium tuberculosis
by using the gamma interferon gene-disrupted (GKO) C57BL/6 mouse. Due to the rapid growth of the infection, statistical differences indicating positive efficacy of active compounds can be seen after only 8 days of treatment. To validate this model, several fluoroquinolones, including ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin, were tested in parallel.
Nonconjugative Transposition of the
vanB
-Containing Tn
5382
-Like Element in
Enterococcus faecium
Authors: Dahl Kristin H. , Røkenes Torunn P. , Lundblad Eirik W. , Sundsfjord Arnfinn 
Published: January 2003

ABSTRACT

The
vanB
2 operon encoding glycopeptide resistance is an integral part of the putative conjugative transposon Tn
5382
. Characterization of clinical glycopeptide resistant derivatives from an epidemic ampicillin-resistant
Enterococcus faecium
strain showed precise chromosomal or plasmid insertions of a
vanB2
-containing Tn
5382
-like element. Conjugative transposition of the Tn
5382
-like element was not demonstrated in retransfer studies.
Clinical Isolates of
Enterobacteriaceae
Producing Extended-Spectrum β-Lactamases: Prevalence of CTX-M-3 at a Hospital in China
Authors: Wang Hui , Kelkar Swathi , Wu Weiyuan , Chen Minjun , Quinn John P. 
Published: January 2003

ABSTRACT

The prevalence of extended-spectrum β-lactamase-producing strains was demonstrated in 5 of 44 (11.4%)
Escherichia coli
, 17 of 43 (39.5%)
Klebsiella pneumoniae
, 3 of 50 (6.0%)
Enterobacter cloacae
, and 2 of 25 (8.0%)
Citrobacter freundii
strains at a teaching hospital in China. Nineteen of these 27 strains expressed CTX-M-3 β-lactamase (pI 8.6). A subset of the clinical isolates expressing the CTX-M-3 enzyme, tested by pulsed-field gel electrophoresis, revealed multiple clones. Five isolates expressed a novel enzyme, SHV-43 (pI 8.0), which had two substitutions (Leu113Phe and Thr149Ser) compared with SHV-1.
Genetic Basis of Antibiotic Resistance in
Streptococcus agalactiae
Strains Isolated in a French Hospital
Authors: Poyart Claire , Jardy Laurence , Quesne Gilles , Berche Patrick , Trieu-Cuot Patrick 
Published: January 2003

ABSTRACT

The genetic basis of antibiotic resistance in 113 unrelated group B streptococci was studied by PCR. Ninety-four strains were resistant to tetracycline-minocycline, and
tet
(M) was detected in 85% of these isolates. Seventeen erythromycin-resistant strains contained the
erm
(B),
erm
(TR), or
mef
(A) gene. Eleven strains exhibited high-level resistance to kanamycin due to the presence of the
aphA3
gene; eight of these strains were also highly resistant to streptomycin;
aad
-
6-
related sequences were detected in seven strains.
Conjugative Plasmid Conferring Resistance to Olaquindox
Authors: Sørensen Anders Hay , Hansen Lars Hestbjerg , Johannesen Elsebetta , Sørensen Søren J. 
Published: January 2003

ABSTRACT

A conjugative plasmid, pOLA52, conferring resistance to the antibiotic growth promoter olaquindox has been isolated from
Escherichia coli
from swine manure. It also confers resistance to ampicillin and chloramphenicol and has a high frequency of transfer between strains of
E. coli
. Plasmid-borne olaquindox resistance has not been demonstrated before.
Growth-Inhibitory Effects of Artesunate, Pyrimethamine, and Pamaquine againstBabesia equiandBabesia caballiin In Vitro Cultures
Authors: Nagai Akiko , Yokoyama Naoaki , Matsuo Tomohide , Bork Sabine , Hirata Haruyuki , Xuan Xuenan , Zhu Yinchang , Claveria Florencia G. , Fujisaki Kozo , Igarashi Ikuo 
Published: January 2003

ABSTRACTThree antimalarial drugs, artesunate, pyrimethamine, and pamaquine, were evaluated for their growth-inhibitory effects againstBabesia equiandBabesia caballiin in vitro culture.B. equiwas more resistant to pyrimethamine thanB. caballi. B. equiwas also found to be more sensitive to artesunate and pamaquine thanB. caballi. Of the three compounds, pyrimethamine gave the most promise for in vivo effectiveness.