Ciprofloxacin resistance in clinical isolates of Salmonella typhimurium obtained from two patients

Piddock, Laura J. V.; Griggs, Deborah; Hall, Matthew C.; Jin, Yu Fang

doi:10.1128/aac.37.4.662

Cited by 96 publications

(81 citation statements)

References 23 publications

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“…A few studies have reported on alterations of outer membrane protein expression or of lipopolysaccharide in quinolone-resistant Salmonella [18,20,56,57]. However, it does not appear clearly from these studies whether such alterations contributed significantly to decreased outer membrane permeability and consecutive quinolone resistance.…”

Section: Decreased Outer Membrane Permeabilitymentioning

confidence: 69%

“…The role in Salmonella quinolone resistance of mutations in the target genes, in particular in gyrA and gyrB, has been confirmed by complementation studies using wild-type genes on plasmids [16,20,23,54,56,57]. It nevertheless remains to be determined what the exact impact of these mutations is on quinolone resistance, as has been done for E. coli constructed isogenic mutants where mutations in gyrA and parC were experimentally introduced in the absence of quinolone selection [4].…”

Section: Target Gene Mutationsmentioning

confidence: 97%

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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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Section: Decreased Outer Membrane Permeabilitymentioning

confidence: 69%

Section: Target Gene Mutationsmentioning

confidence: 97%

Mechanisms of quinolone resistance in Salmonella

Cloeckaert

Chaslus-Dancla

2001

Vet. Res.

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“…Antibiotic resistance, particularly to ciprofloxacin [minimum inhibitory concentration (MIC) ≥0.5 μg/mL], occurred and increased in the isolates along the time course of infection (Table 1; susceptibility data for other antibiotics have been previously published and are shown in Table S2) (14,15,18). Previously, the MDR was attributed to increased expression of the acrB transcript (18).…”

Section: Resultsmentioning

confidence: 99%

“…S1) (14,15). The isolates were obtained from a 52-y-old male patient admitted for repair of a leaking abdominal aortic aneurysm graft.…”

mentioning

confidence: 99%

AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

Blair

Bavro

Ricci

et al. 2015

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

164

165

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The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre-and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrABTolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.efflux | antimicrobial resistance | AcrB | whole genome sequencing

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“…In contrast to the findings in Enterobacter aerogenes and E. coli (8), ramA-mediated MDR in 5408-cip was not associated with downregulation of porins. Few studies have investigated OmpF expression in fluoroquinolone-resistant Salmonella, and its contribution to resistance is unclear (14,29,35). Only one study to date has documented alterations in the LPS profile in fluoroquinolone-resistant Salmonella, and the authors suggested that the increase in the proportion of long O-chain LPSs observed could result in a lower level of antibiotic accessibility to the porins (14).…”

Section: Discussionmentioning

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 resistance in clinical isolates of Salmonella typhimurium obtained from two patients

Cited by 96 publications

References 23 publications

Mechanisms of quinolone resistance in Salmonella

Mechanisms of quinolone resistance in Salmonella

AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

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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