Novel role of Acinetobacter baumannii RND efflux transporters in mediating decreased susceptibility to biocides

Rajamohan, Govindan; Srinivasan, Vijaya Bharathi; Gebreyes, Wondwossen A.

doi:10.1093/jac/dkp427

Cited by 93 publications

(98 citation statements)

References 8 publications

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“…1 and Table S2). The AdeABC efflux system has been shown to mediate resistance to chlorhexidine in clinical A. baumannii isolates (6). Studies conducted in P. aeruginosa and Burkholderia cenocepacia have shown that overexpression of homologous RND efflux systems is a major part of the transcriptional response to chlorhexidine stress (9, 10), indicating that these proteins are primary chlorhexidine resistance factors across a number of Gram-negative genera.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins

Hassan

Jackson

Penesyan

et al. 2013

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

141

205

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Significance Drug resistance is an increasing problem in clinical settings with some bacterial pathogens now resistant to virtually all available drugs. Chlorhexidine is a commonly used antiseptic and disinfectant in hospital environments, and there is increasing resistance to chlorhexidine seen in some pathogenic bacteria, such as Acinetobacter baumannii . This paper examines the global gene expression of A. baumannii in response to chlorhexidine exposure and identifies a gene that we demonstrate to mediate chlorhexidine resistance. Biochemical investigation reveals that this gene encodes a previously uncharacterized type of drug efflux pump that actively transports chlorhexidine out of the cell.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins

Hassan

Jackson

Penesyan

et al. 2013

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

141

205

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“…AdeIJK contributes to both intrinsic and acquired MDR (502, 528,530,533,542,543). Its inactivation in a wild-type strain caused mostly 4-to 16-fold reductions of MICs of ␤-lactams (aztreonam, ceftazidime, cefepime, and ticarcillin), chloramphenicol, clindamycin, erythromycin, fluoroquinolones (norfloxacin and ciprofloxacin), and tetracyclines (tetracycline, minocycline, and tigecycline) (184,542).…”

Section: Acinetobacter Sppmentioning

confidence: 99%

“…Its inactivation in a wild-type strain caused mostly 4-to 16-fold reductions of MICs of ␤-lactams (aztreonam, ceftazidime, cefepime, and ticarcillin), chloramphenicol, clindamycin, erythromycin, fluoroquinolones (norfloxacin and ciprofloxacin), and tetracyclines (tetracycline, minocycline, and tigecycline) (184,542). AdeIJK also mediates resistance to biocides, including the frequently used biocides chlorhexidine and triclosan and other disinfectants in hospitals (530,544). In vitro selection of AdeIJK-overproducing mutants by triclosan was recently demonstrated (544).…”

Section: Acinetobacter 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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“…Besides, nonenzymatic mechanisms, like modifications of antibiotic membrane permeability, usually act in synergy with these enzymes to confer a high-level resistance phenotype (18,20,53,60). These permeability modifications could be to the overexpression of multidrug RND efflux pumps (12,33,34,47,48,50,57) and/or modifications of outer membrane protein (OMP) expression or structure (9,29,30,39,40,42,54).…”

mentioning

confidence: 99%

Deciphering the Function of the Outer Membrane Protein OprD Homologue of Acinetobacter baumannii

Catel-Ferreira

Nehmé

Molle

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTThe increasing number of carbapenem-resistantAcinetobacter baumanniiisolates is a major cause for concern which restricts therapeutic options to treat severe infections caused by this emerging pathogen. To identify the molecular mechanisms involved in carbapenem resistance, we studied the contribution of an outer membrane protein homologue of thePseudomonas aeruginosaOprD porin. Suspected to be the preferred pathway of carbapenems inA. baumannii, theoprDhomologue gene was inactivated in strain ATCC 17978. Comparison of wild-type and mutant strains did not confirm the expected increased resistance to any antibiotic tested. OprD homologue sequence analysis revealed that this protein actually belongs to an OprD subgroup but is closer to theP. aeruginosaOprQ protein, with which it could share some functions, e.g., allowing bacterial survival under low-iron or -magnesium growth conditions or under poor oxygenation. We thus overexpressed and purified a recombinant OprD homologue protein to further examine its functional properties. As a specific channel, this porin presented rather low single-channel conductance, i.e., 28 pS in 1 M KCl, and was partially closed by micro- and millimolar concentrations of Fe3+and Mg2+, respectively, but not by imipenem and meropenem or basic amino acids. TheA. baumanniiOprD homologue is likely not involved in the carbapenem resistance mechanism, but as an OprQ-like protein, it could contribute to the adaptation of this bacterium to magnesium- and/or iron-depleted environments.

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Novel role of Acinetobacter baumannii RND efflux transporters in mediating decreased susceptibility to biocides

Abstract: This is the first study demonstrating the role of efflux pumps in mediating decreased susceptibility to disinfectants and other chemical substrates in A. baumannii.

Cited by 93 publications

References 8 publications

Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins

Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins

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

Deciphering the Function of the Outer Membrane Protein OprD Homologue of Acinetobacter baumannii

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