First Description of an RND-Type Multidrug Efflux Pump in Achromobacter xylosoxidans, AxyABM

Bador, Julien; Amoureux, Lucie; Duez, Jean-Marie; Drabowicz, Anthony; Siébor, Eliane; Llanes, Catherine; Neuwirth, Catherine

doi:10.1128/aac.00341-11

Cited by 68 publications

(69 citation statements)

References 25 publications

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“…It is an opportunistic pathogen that can cause a wide variety of infections in immunocompromised patients (7)(8)(9)(10) but is mainly recovered from CF patients' airways. As previously reported, this species is innately resistant to cephalothin, cefoxitin, cefotaxime, aztreonam, and aminoglycosides (11,12). Acquired resistance to carbapenems, ceftazidime, and ciprofloxacin is frequent, dramatically limiting therapeutic choices (13,14).…”

mentioning

confidence: 83%

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Amoureux

Bador

Fardeheb

et al. 2013

Appl Environ Microbiol

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Achromobacter xylosoxidans is an aerobic nonfermentative Gram-negative rod considered an important emerging pathogen among cystic fibrosis (CF) patients worldwide and among immunocompromised patients. This increased prevalence remains unexplained, and to date no environmental reservoir has been identified. The aim of this study was to identify potential reservoirs of A. xylosoxidans in hospital, domestic, and outdoor environments and to compare the isolates with clinical ones. From 2011 to 2012, 339 samples were collected in Dijon's university hospital, in healthy volunteers' homes in the Dijon area, and in the outdoor environment in Burgundy (soil, water, mud, and plants). We designed a protocol to detect A. xylosoxidans in environmental samples based on a selective medium: MCXVAA (MacConkey agar supplemented with xylose, vancomycin, aztreonam, and amphotericin B). Susceptibility testing, genotypic analysis by pulsed-field gel electrophoresis, and bla OXA-114 sequencing were performed on the isolates. A total of 50 strains of A. xylosoxidans were detected in hospital (33 isolates), domestic (9 isolates), and outdoor (8 isolates) samples, mainly in hand washing sinks, showers, and water. Most of them were resistant to ciprofloxacin (49 strains). Genotypic analysis and bla OXA-114 sequencing revealed a wide diversity among the isolates, with 35 pulsotypes and 18 variants of oxacillinases. Interestingly, 10 isolates from hospital environment were clonally related to clinical isolates previously recovered from hospitalized patients, and one domestic isolate was identical to one recovered from a CF patient. These results indicate that A. xylosoxidans is commonly distributed in various environments and therefore that CF patients or immunocompromised patients are surrounded by these reservoirs.

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confidence: 83%

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Amoureux

Bador

Fardeheb

et al. 2013

Appl Environ Microbiol

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“…The latter include 4 RND systems, additional tripartite efflux systems, and an ABC-type macrolide-specific MacAB transporter (605). Two RND pumps, AxyABM and AxyXY-OprZ, were identified to mediate MDR (606). Inactivation of AxyB produced up to a 20-fold reduction of the MIC values of several third-generation cephalosporins, with no changes in susceptibility to the aminoglycosides amikacin and tobramycin (606).…”

Section: Achromobacter Sppmentioning

confidence: 99%

“…Two RND pumps, AxyABM and AxyXY-OprZ, were identified to mediate MDR (606). Inactivation of AxyB produced up to a 20-fold reduction of the MIC values of several third-generation cephalosporins, with no changes in susceptibility to the aminoglycosides amikacin and tobramycin (606). However, the disruption of AxyY rendered a wild-type strain highly susceptible to aminoglycosides (16-to 128-fold MIC decreases for amikacin, gentamicin, netilmicin, and tobramycin), doripenem, erythromycin, and tetracycline (all with 4-fold MIC reductions).…”

Section: Achromobacter Sppmentioning

confidence: 99%

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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“…AXX-A has been used in previous studies to characterize AxyABM and AxyXY-OprZ RND-type efflux systems (21,22). It was used in the present work to examine the role of axyZ in the expression of axyXY-oprZ by gene deletion.…”

Section: Methodsmentioning

confidence: 99%

“…scribed to date in Achromobacter and contribute to its intrinsic antibiotic resistance: AxyABM and AxyXY-OprZ (21,22). The latter system is encoded by three chromosomal genes: axyX, axyY, and oprZ.…”

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confidence: 99%

Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin

Bador

Neuwirth

Grangier

et al. 2017

Antimicrob Agents Chemother

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AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ. An in-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system, including aminoglycosides, cefepime, fluoroquinolones, tetracyclines, and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ. Moreover, we identified an amino acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract colonization in a cystic fibrosis (CF) patient. This substitution, also detected in three other strains exposed in vitro to tobramycin, led to an increase in the axyY transcription level (5-to 17-fold) together with an increase in antibiotic resistance level. This overproduction of AxyXY-OprZ is the first description of antibiotic resistance acquisition due to modification of a chromosomally encoded mechanism in Achromobacter and might have an impact on the management of infected CF patients. Indeed, tobramycin is widely used for aerosol therapy within this population, and we have demonstrated that it easily selects mutants with increased MICs of not only aminoglycosides but also fluoroquinolones, cefepime, and tetracyclines.

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First Description of an RND-Type Multidrug Efflux Pump in Achromobacter xylosoxidans, AxyABM

Cited by 68 publications

References 25 publications

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

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

Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin

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