Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins

Hassan, Karl A.; Jackson, Scott M.; Penesyan, Anahit; Patching, Simon G.; Tetu, Sasha G.; Eijkelkamp, Bart A.; Brown, Melissa H.; Henderson, Peter J. F.; Paulsen, Ian T.

doi:10.1073/pnas.1317052110

Cited by 145 publications

(225 citation statements)

References 33 publications

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“…The copresence of the Tet(A) pump and Tet(M) for ribosomal protection was also noted (16). Lastly, a new type of efflux pump, AceI, was found to mediate resistance to chlorhexidine (563). Chlorhexidine itself also induces the expression of AceI and AdeABC.…”

Section: Acinetobacter Sppmentioning

confidence: 89%

“…Chlorhexidine itself also induces the expression of AceI and AdeABC. AceI belongs to the bacterial transmembrane pair family and is grouped as a prototype member of the proteobacterial chlorhexidine efflux family (563). Similarly, the exposure of Acinetobacter baylyi to chlorhexidine also induced resistance to chlorhexidine and oxidants (564), which could potentially be attributed to efflux pumps.…”

Section: Acinetobacter 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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Section: Acinetobacter Sppmentioning

confidence: 89%

Section: Acinetobacter Sppmentioning

confidence: 99%

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

2015

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“…Other highly upregulated genes include predicted metal transport systems and a predicted ABC transport system of unknown function that appears to be encoded by a mobile genetic element. The specific roles of these transport systems in the H-CHG stress response remain to be determined; possibilities include chlorhexidine efflux (note that a new family of chlorhexidine efflux proteins was recently identified for Gram-negative bacteria [67,68]), transport of metals to maintain redox balance in the cell, or transport of cell wall-related metabolites. Future studies will compare the transcriptomic response of E. faecium to H-CHG to that for CHG and sodium gluconate, which will help to determine which specific components of H-CHG are responsible for the transcriptional changes observed.…”

Section: Discussionmentioning

confidence: 99%

Chlorhexidine Induces VanA-Type Vancomycin Resistance Genes in Enterococci

Bhardwaj

Ziegler

Palmer

2016

Antimicrob Agents Chemother

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Chlorhexidine is a bisbiguanide antiseptic used for infection control. Vancomycin-resistant E. faecium (VREfm) is among the leading causes of hospital-acquired infections. VREfm may be exposed to chlorhexidine at supra-and subinhibitory concentrations as a result of chlorhexidine bathing and chlorhexidine-impregnated central venous catheter use. We used RNA sequencing to investigate how VREfm responds to chlorhexidine gluconate exposure. Among the 35 genes upregulated >10-fold after 15 min of exposure to the MIC of chlorhexidine gluconate were those encoding VanA-type vancomycin resistance (vanHAX) and those associated with reduced daptomycin susceptibility (liaXYZ). We confirmed that vanA upregulation was not strain or species specific by querying other VanA-type VRE. VanB-type genes were not induced. The vanH promoter was found to be responsive to subinhibitory chlorhexidine gluconate in VREfm, as was production of the VanX protein. Using vanH reporter experiments with Bacillus subtilis and deletion analysis in VREfm, we found that this phenomenon is VanR dependent. Deletion of vanR did not result in increased chlorhexidine susceptibility, demonstrating that vanHAX induction is not protective against chlorhexidine. As expected, VanA-type VRE is more susceptible to ceftriaxone in the presence of sub-MIC chlorhexidine. Unexpectedly, VREfm is also more susceptible to vancomycin in the presence of subinhibitory chlorhexidine, suggesting that chlorhexidine-induced gene expression changes lead to additional alterations in cell wall synthesis. We conclude that chlorhexidine induces expression of VanA-type vancomycin resistance genes and genes associated with daptomycin nonsusceptibility. Overall, our results indicate that the impacts of subinhibitory chlorhexidine exposure on hospital-associated pathogens should be further investigated in laboratory studies.

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“…22,24 Previous studies on the in vitro activity of chlorhexidine against various bacteria found that the minimum inhibitory concentration of chlorhexidine for P. aeruginosa (5-60 µg/mL) was higher than that for S. aureus (0.5-1 µg/mL) and chlorhexidine-resistant A. baumannii and E. coli owing to a drug efflux pump. 25,26 In subgroup analyses, MDR bacterial colonization at enrollment had significantly fewer favorable events compared with no-MDR bacterial colonization at enrollment, and the MDR bacterial colonization was the major risk factor of unfavorable outcomes. The reason might be that MDR gram-negative bacteria isolated from the ICU patients in this study were resistant to chlorhexidine.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Chlorhexidine Wipes for the Prevention of Multidrug-Resistant Bacterial Colonization and Hospital-Acquired Infections in Intensive Care Unit Patients: A Randomized Trial in Thailand

Boonyasiri

Thaisiam

Permpikul

et al. 2015

Infect. Control Hosp. Epidemiol.

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Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins

Cited by 145 publications

References 33 publications

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

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

Chlorhexidine Induces VanA-Type Vancomycin Resistance Genes in Enterococci

Effectiveness of Chlorhexidine Wipes for the Prevention of Multidrug-Resistant Bacterial Colonization and Hospital-Acquired Infections in Intensive Care Unit Patients: A Randomized Trial in Thailand

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