Role of the CmeABC efflux pump in the emergence of fluoroquinolone-resistant Campylobacter under selection pressure

Yan, Meiguan; Şahin, Orhan; Lin, Jun; Zhang, Qijing

doi:10.1093/jac/dkl412

Cited by 93 publications

(92 citation statements)

References 39 publications

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“…The cmeABC operon encodes an important drug efflux pump in C. jejuni (22), and it is negatively regulated by CmeR, which binds to a 16-base inverted repeat (IR) sequence (TGTAATA[or T]TTTATTACA; the repeat sequences are underlined) named CmeR-Box located in the promoter region of the cmeABC operon (16,23). In contrast with previous studies (16, 24), we did not find mutations inactivating CmeR (16).…”

contrasting

confidence: 94%

Correlation between gyrA and CmeR Box Polymorphism and Fluoroquinolone Resistance in Campylobacter jejuni Isolates in China

Zhāng

Cheng

Luo

et al. 2017

Antimicrob Agents Chemother

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Sequence analysis of 79 ciprofloxacin-resistant Campylobacter jejuni isolates collected in China showed resistance-related sequence variations in gyrA and CmeR-Box. All the isolates contain an identical Thr-86-Ile substitution in GyrA. Several novel CmeR-Box variations, including point substitutions, deletion, and insertion, were identified. The point insertion or deletion led to dramatically reduced binding of CmeR to the cmeABC promoter, which significantly increases the expression of cmeABC and contributes to the high fluoroquinolone resistance.

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contrasting

confidence: 94%

Correlation between gyrA and CmeR Box Polymorphism and Fluoroquinolone Resistance in Campylobacter jejuni Isolates in China

Zhāng

Cheng

Luo

et al. 2017

Antimicrob Agents Chemother

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“…The CmeABC system is the most characterized RND pump in campylobacters and is responsible for both intrinsic and acquired MDR, including resistance to bile salts (654,655). It is distributed in diverse isolates of animals and humans that are resistant to macrolides, fluoroquinolones, and tetracyclines (16,(656)(657)(658)(659)(660)(661). Inactivation of CmeABC reduces significantly the in vitro emergence of fluoroquinolone-resistant mutants, while its overproduction facilitates such selection (659).…”

Section: Campylobacter Sppmentioning

confidence: 99%

“…It is distributed in diverse isolates of animals and humans that are resistant to macrolides, fluoroquinolones, and tetracyclines (16,(656)(657)(658)(659)(660)(661). Inactivation of CmeABC reduces significantly the in vitro emergence of fluoroquinolone-resistant mutants, while its overproduction facilitates such selection (659). Although the contribution of another RND pump, CmeDEF, to intrinsic resistance is likely masked by CmeABC, the two pumps interplay synergistically in providing resistance (662).…”

Section: Campylobacter Sppmentioning

confidence: 99%

“…In vitro stepwise exposures of C. jejuni to escalating levels of erythromycin or tylosin have generated a variety of macrolide-resistant mutants (668). The mutations in ribosome proteins L4 and L22 occurred early during this selection (low resistance level, with an erythromycin MIC of 8 to 16 g/ml), followed by CmeABC overproduction (intermediate level, with an erythromycin MIC of 32 to 256 g/ ml), and finally accompanied by mutations in the 23S rRNA genes (high level, with an erythromycin MIC of Ն256 g/ml), highlighting that efflux mechanisms likely facilitate the emergence of highlevel macrolide resistance, similar to that of high-level fluoroquinolone resistance (659). CmeABC overexpression was partially a result of single-residue changes in the C terminus of the repressor CmeR (668).…”

Section: Campylobacter Sppmentioning

confidence: 99%

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The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…está relacionada principalmente à mutação Tre-86-Ile na RDRQ do gene gyrA da DNA girase, de acordo com vários autores (Yang et al 2006, Qin et al 2011, Iovine 2013, Frasao & Aquino 2014. Entretanto, outras mutações (Tre-86-Ile, Asp-90-Asn, Ala-70-Tre, Asp-85-Tir, Pro-104-Ser) nessa região já foram descritas como relacionadas à resistência em Campylobacter, além de mutações no gene parC, da topisomerase IV e da ação exacerbada da bomba de efluxo CmeABC devido à mutação no gene cmeR (Bachoual et al 2001, Piddock et al 2003, Yang et al 2006, Qin et al 2011, Wieczorek & Osek 2013, Iovine 2013, Hungaro et al 2015.…”

Section: Introductionunclassified

Detecção de resistência às fluoroquinolonas em Campylobacter isolados de frangos de criação orgânica

et al. 2015

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ABSTRACT.-Frasão B.S., Côrtes L.R., Nascimento E.R., Cunha N.C., Almeida V. Studies have shown that resistance to quinolones in Campylobacter strains is related with Threonine-86-Isoleucine mutation. In order to investigate the presence of this mutation in sensitive and resistant Campylobacter strains to ciprofloxacin and enrofloxacin, the cecal contents of 80 broilers from organic raising chickens, slaughtered under State Inspection Service (S.I.S) of the State of Rio de Janeiro, were collected and tested for the presence of Campylobacter. The determination of ciprofloxacin and enrofloxacin susceptibility was done by disk diffusion and agar dilution methods for determining the Minimum Inhibitory Concentration (MIC). The detection of mutation in Quinolone Resistance Determinant Region (QRDR) in gyrA gene was done by sequencing. Campylobacter was isolated from 100% of the samples, being 68.75% C. jejuni and 31.25% C. coli. By the disk diffusion method, resistance to ciprofloxacin was observed in all isolates and 56.25% of the strains were resistant to enrofloxacin. By agar dilution method, all strains were resistant to ciprofloxacin (MIC ≥ 16µg/mL to ≥ 64µg/mL) and full and intermediate resistance to enrofloxacin was detected in 42.50% (MIC ≥ 4-32μg/mL) and 38.75% (MIC =2μg/mL) of the strains, respectively. Mutation Thr-86-Ile was observed in 100% of the isolates investigated. In addition to this mutation, others no silent mutations and silent mutations (His-81-His, Ser-119-Ser, Ala-120-Ala, Phe-99-Phe, Ala-122-Ala, Gly-74-Gly, Ile-77-Ile, Ala-91-Ala, Leu-92-Leu, Val-93-Val, Ile-106-Ile, Thr-107-Thr, Gly-113-Gly, Ile-115-Ile, Gly-110-Gly) were detected. All the enrofloxacin--sensitive strains by the phenotypic methods had the Thr-86 to Ile substitution, which suggests other mechanisms contributing to enrofloxacin resistance in Campylobacter.

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Role of the CmeABC efflux pump in the emergence of fluoroquinolone-resistant Campylobacter under selection pressure

Abstract: CmeABC is not only important for maintaining high-level resistance to FQs but also contributes significantly to the emergence of FQ-resistant mutants. Inhibition of this efflux pump may prevent the emergence of clinically relevant FQ-resistant Campylobacter mutants.

Cited by 93 publications

References 39 publications

Correlation between gyrA and CmeR Box Polymorphism and Fluoroquinolone Resistance in Campylobacter jejuni Isolates in China

Correlation between gyrA and CmeR Box Polymorphism and Fluoroquinolone Resistance in Campylobacter jejuni Isolates in China

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Detecção de resistência às fluoroquinolonas em Campylobacter isolados de frangos de criação orgânica

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