Ineffectiveness of Topoisomerase Mutations in Mediating Clinically Significant Fluoroquinolone Resistance in
            <i>Escherichia coli</i>
            in the Absence of the AcrAB Efflux Pump

Oethinger, Margret; Kern, Winfried V.; Jellen-Ritter, Angelika; McMurry, Laura M.; Levy, Stuart B.

doi:10.1128/aac.44.1.10-13.2000

Cited by 191 publications

(137 citation statements)

References 29 publications

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“…This finding may have baring on the observation that drug efflux pump deficiency greatly slows down the evolution of target resistance mutations among pathogens (5,6,8,17). Our analysis suggests, in other words, target resistance masking in combination with growth-bistability to be a previously unrecognized cause of delayed drug resistance development among pathogens under drug efflux pump deficient conditions.…”

mentioning

confidence: 70%

“…Experiments show that the drug susceptibility of pathogens increases dramatically upon reduction of drug efflux pump efficiency by either genetic manipulation (4,5) or addition of efflux pump inhibitors (6)(7)(8)(9). This feature of drug efflux pump deficiency is intuitively obvious, but recent findings for the ribosome targeting macrolide antibiotic erythromycin suggest the existence of more subtle aspects of the interplay between drug efflux pump efficiency and drug susceptibility.…”

mentioning

confidence: 99%

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Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Fange

Nilsson²,

Tenson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to ''mask'' the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens.antibiotic resistance ͉ efflux pump inhibition ͉ macrolides

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mentioning

confidence: 70%

mentioning

confidence: 99%

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Fange

Nilsson²,

Tenson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The relative involvement of these different mechanisms in the resistance to fluoroquinolones is questionable [3,25,43].…”

Section: Resistance To Fluoroquinolonesmentioning

confidence: 99%

Use of antimicrobials in veterinary medicine and mechanisms of resistance

2001

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-This review deals with the application of antimicrobial agents in veterinary medicine and food animal production and the possible consequences arising from the widespread and multipurpose use of antimicrobials. The various mechanisms that bacteria have developed to escape the inhibitory effects of the antimicrobials most frequently used in the veterinary field are reported in detail. Resistance of bacteria to tetracyclines, macrolide-lincosamide-streptogramin antibiotics, β-lactam antibiotics, aminoglycosides, sulfonamides, trimethoprim, fluoroquinolones and chloramphenicol/florfenicol is described with regard to enzymatic inactivation, decreased intracellular drug accumulation and modification/protection/replacement of the target sites. In addition, basic information is given about mobile genetic elements which carry the respective resistance genes, such as plasmids, transposons, and gene cassettes/integrons, and their ways of spreading via conjugation, mobilisation, transduction, and transformation.antibiotic therapy / growth promotion / resistance mechanism / resistance gene / gene transfer Résumé -Utilisation d'agents antimicrobiens en médecine vétérinaire et mécanismes de résis-tance. Cette revue présente les différents buts pour lesquels les agents antimicrobiens sont utilisés en médecine vétérinaire, dans les élevages d'animaux entrant dans la chaîne alimentaire et les possibles conséquences de cette large utilisation. Une synthèse est faite des différents mécanismes de résis-tance développés par les bactéries, comme l'inactivation enzymatique, la diminution de la concentration intracellulaire de l'antibiotique, les modification/protection/déplacement de cible, qui permettent d'échapper à l'action des antibiotiques les plus fréquemment utilisés dans le domaine vétérinaire :

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“…It is particularly interesting to note that in E. coli, inactivation of the AcrAB efflux pump makes resistant strains, including those with target gene mutations, hypersusceptible to fluoroquinolones and certain other unrelated drugs [52]. Thus in the absence of the AcrAB efflux pump, gyrase mutations fail to produce clinically relevant levels of fluoroquinolone resistance [52].…”

Section: Escaping Quinolone Resistancementioning

confidence: 99%

Mechanisms of quinolone resistance in Salmonella

Cloeckaert

Chaslus-Dancla

2001

Vet. Res.

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-As in other Gram-negative bacteria, mechanisms of resistance to quinolones in Salmonella include target gene mutations, active efflux, and decreased outer membrane permeability. However, the exact contribution of these individual mechanisms to resistance, which may nevertheless interplay to reach high-level resistance, has not yet clearly been defined as in other bacteria such as Escherichia coli. This paper reviews the current state of knowledge of quinolone resistance mechanisms in Salmonella by comparison with that of E. coli and future directions of research with particular attention to the recent development of efflux pump inhibitors as possible means of avoiding the emergence and spread of fluoroquinolone resistance.Salmonella / quinolone / resistance / mechanism Résumé -Mécanismes de résistance aux quinolones chez Salmonella. Comme chez les autres bactéries Gram-négatives les mécanismes de résistance aux quinolones chez Salmonella comprennent les mutations dans les gènes cibles, l'efflux actif, et une diminution de la perméabilité de la membrane externe. Cependant la contribution exacte de ces mécanismes individuels, qui peuvent néanmoins interagir pour atteindre des niveaux de résistance élevés, n'a pas encore été clairement définie comme chez d'autres bactéries telle que Escherichia coli. Cette revue présente l'état actuel des connaissances des mécanismes de résistance chez Salmonella par comparaison avec E. coli et des perspectives futures de recherche avec une attention particulière au développement récent d'inhibiteurs de pompes d'efflux comme moyen possible pour éviter l'émergence et la diffusion de la résistance aux fluoroquinolones.Salmonella / quinolone / résistance / mécanisme Vet. Res. 32 (2001) 291-300 291

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Ineffectiveness of Topoisomerase Mutations in Mediating Clinically Significant Fluoroquinolone Resistance in Escherichia coli in the Absence of the AcrAB Efflux Pump

Cited by 191 publications

References 29 publications

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Use of antimicrobials in veterinary medicine and mechanisms of resistance

Mechanisms of quinolone resistance in Salmonella

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