Ciprofloxacin-Resistant
            <i>Salmonella enterica</i>
            Serovar Typhimurium Strains Are Difficult To Select in the Absence of AcrB and TolC

Ricci, Vito; Tzakas, Peter; Buckley, Anthony M.; Coldham, Nick C.; Piddock, Laura J. V.

doi:10.1128/aac.50.1.38-42.2006

Cited by 117 publications

(103 citation statements)

References 42 publications

(58 reference statements)

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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: 69%

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: 69%

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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“…Deletion of acrD or acrF from S. enterica serovar Typhimurium had little effect on the MICs of clinically relevant antibiotics (40). However, it was shown that when either of these genes was deleted, AcrB expression was increased (40); likewise, when acrB was deleted, expression of acrD or acrF increased (40,185). It may be that the bacterium can compensate for the lack of AcrD or AcrF, and consequently there is no effect on MICs.…”

Section: Efflux Pumps Of Clinically Relevant Bacteria That Confer Mdrmentioning

confidence: 95%

“…1). Mutants of S. enterica serovar Typhimurium that lack various efflux pump genes have been constructed (15,25,40,185). Mutants lacking AcrB were hypersusceptible to quinolones, tetracycline, chloramphenicol, bile salts, SDS, Triton-X100, acriflavine, ethidium bromide, cetyltrimethylammonium bromide (CTAB), and triclosan.…”

Section: Efflux Pumps Of Clinically Relevant Bacteria That Confer Mdrmentioning

confidence: 99%

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

2006

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SUMMARY Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed.

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“…Ciprofloxacin-resistant mutants (104-cip and 5408-cip) were selected from serovar Enteritidis strains 104 and 5408. Salmonella enterica serovar Typhimurium knockout strains L110 acrB::aph, L130 marA::aph, L133 ramA::aph, and L135 soxS::aph derived from SL1344 (12,41) and donor E. coli strains carrying the plasmids pBP513 gyrA ϩ , pBP548 gyrB ϩ , and pBP568 parE ϩ were also used and kindly provided to L. Piddock by P. Heisig (15).…”

Section: Methodsmentioning

confidence: 99%

Multiple Regulatory Pathways Associated with High-Level Ciprofloxacin and Multidrug Resistance in Salmonella enterica Serovar Enteritidis: Involvement of ramA and Other Global Regulators

O'Regan

Quinn

Pagès

et al. 2009

Antimicrob Agents Chemother

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Mechanisms of antibiotic resistance were examined in nalidixic acid-resistant Salmonella enterica serovar Enteritidis field isolates displaying decreased susceptibility to ciprofloxacin and in in vitro-derived ciprofloxacin-resistant mutants (104-cip and 5408-cip). All field isolates harbored a single gyrA mutation (D87Y). Deletion of acrB and complementation with wild-type gyrA increased quinolone susceptibility. Selection for ciprofloxacin resistance was associated with the development of an additional gyrA (S83F) mutation in 104-cip, novel gyrB (E466D) and parE (V461G) mutations in 5408-cip, overexpression of acrB and decreased susceptibility to nonquinolone antibiotics in both mutants, and decreased OmpF production and altered lipopolysaccharide in 104-cip. Complementation of mutated gyrA and gyrB with wild-type alleles restored susceptibility to quinolones in 104-cip and significantly decreased the ciprofloxacin MIC in 5408-cip. Complementation of parE had no effect on quinolone MICs. Deletion of acrB restored susceptibility to ciprofloxacin and other antibiotics tested. Both soxS and marA were overexpressed in 104-cip, and ramA was overexpressed in 5408-cip. Inactivation of each of these global regulators lowered ciprofloxacin MICs, decreased expression of acrB, and restored susceptibility to other antibiotics. Mutations were found in soxR (R20H) and in soxS (E52K) in 104-cip and in ramR (G25A) in 5408-cip. In conclusion, both efflux activity and a single gyrA mutation contribute to nalidixic acid resistance and reduced ciprofloxacin sensitivity. Ciprofloxacin resistance and decreased susceptibility to multiple antibiotics can result from different genetic events leading to development of target gene mutations, increased efflux activity resulting from differential expression of global regulators associated with mutations in their regulatory genes, and possible altered membrane permeability.

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Ciprofloxacin-Resistant Salmonella enterica Serovar Typhimurium Strains Are Difficult To Select in the Absence of AcrB and TolC

Cited by 117 publications

References 42 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

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

Multiple Regulatory Pathways Associated with High-Level Ciprofloxacin and Multidrug Resistance in Salmonella enterica Serovar Enteritidis: Involvement of ramA and Other Global Regulators

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