Efflux-mediated antimicrobial resistance

Journal of Antimicrobial Chemotherapy (2005) 56, 20–51 doi:10.1093/jac/dki171 Advance Access publication 24 May 2005 Efflux-mediated antimicrobial resistance Keith Poole* Department of Microbiology & Immunology, Queen’s University, Kingston, ON, Canada K7L 3N6 Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious disease. And while true biocide resistance is as yet unrealized, in vitro and in vivo episodes of reduced biocide susceptibility are common and the history of antibiotic resistance should not be ignored in the development and use of biocidal agents. Efflux mechanisms of resistance, both drug specific and multidrug, are important determinants of intrinsic and/or acquired resistance to these antimicrobials, with some accommodating both antibiotics and biocides. This latter raises the spectre (as yet generally unrealized) of biocide selection of multiple antibiotic-resistant organisms. Multidrug efflux mechanisms are broadly conserved in bacteria, are almost invariably chromosome-encoded and their expression in many instances results from mutations in regulatory genes. In contrast, drug-specific efflux mechanisms are generally encoded by plasmids and/or other mobile genetic elements (transposons, integrons) that carry additional resistance genes, and so their ready acquisition is compounded by their association with multidrug resistance. While there is some support for the latter efflux systems arising from efflux determinants of self-protection in antibiotic-producing Streptomyces spp. and, thus, intended as drug exporters, increasingly, chromosomal multidrug efflux determinants, at least in Gram-negative bacteria, appear not to be intended as drug exporters but as exporters with, perhaps, a variety of other roles in bacterial cells. Still, given the clinical significance of multidrug (and drug-specific) exporters, efflux must be considered in formulating strategies/approaches to treating drug-resistant infections, both in the development of new agents, for example, less impacted by efflux and in targeting efflux directly with efflux inhibitors. Keywords: efflux, resistance, antimicrobials, antibiotics, biocides, multidrug discussing all efflux mechanisms as determinants of resistance to specific, clinically-relevant antimicrobials. It is hoped that this will provide some insights vis-à-vis the probable clinical significance of drug-specific versus multidrug efflux systems as regards resistance to a given antimicrobial. While the emphasis is on the clinical relevance of efflux mechanisms of resistance, the probable role of Gram-negative multidrug efflux systems in other cellular processes is also addressed. The interested reader is referred to recent reviews of antimicrobial37 and multidrug37–41 efflux for additional information. Introduction While antimicrobials have proven invaluable in the management of bacterial infectious disease, resistance to these agents actually predates the introduction of the first true antibiotic (penicillin) into clinical usage,1 and resistance continues to compromise the use of old and new antimicrobials alike.2–8 The clinical impact of resistance is immense, characterized by increased cost, length of hospital stay and mortality,9–19 often as a result of inappropriate initial antimicrobial therapy.19–24 Resistance to antibiotics occurs typically as a result of drug inactivation/modification, target alteration and reduced accumulation owing to decreased permeability and/or increased efflux.25–27 It may be an innate feature of an organism or, when it is not, occurs as the result of mutation or the acquisition of exogenous resistance genes.28,29 Specific growth states (e.g. biofilm formation30–34 and anaerobiosis35,36) can also negatively impact antimicrobial susceptibility. While biocidal agents generally remain effective at ‘at use’ concentrations, numerous mechanisms of reduced susceptibility have, nonetheless, been reported in bacteria.25 This review provides an overview of efflux determinants of antimicrobial (antibiotic and biocide) resistance, both agent-specific and multidrug, emphasizing recent advances and Efflux-mediated resistance to antibiotics The last of the resistance mechanisms to be identified, efflux was first described as a mechanism of resistance to tetracycline in Escherichia coli,42,43 with the plasmid-encoded single component Tet protein export of tetracycline (complexed with Mg2+ it turns out) across the cytoplasmic membrane sufficient for resistance. In the intervening years, numerous plasmid- and chromosomeencoded efflux mechanisms, both agent- or class-specific and multidrug have been described in a variety of organisms where they are increasingly appreciated as important determinants of ............................................................................................................................................................................................................................................................................................................................................................................................................................. *Tel: +1-613-533-6677; Fax: +1-613-533-6796; E-mail: ............................................................................................................................................................................................................................................................................................................................................................................................................................. 20
The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: Review that includes a periplasmic membrane fusion protein (MFP) and an outer membrane protein [now called outer membrane factor (OMF)], an organization also seen on occasion with ABC [e.g. the macrolide-specific MacAB-TolC efflux system (Table 1)] and MF [e.g. the VceAB multidrug efflux system of Vibrio cholerae46] family exporters (Figure 2). Members of all but the ABC family (whose members hydrolyse ATP to drive drug efflux) function as secondary transporters, catalysing drug– ion (H+ or Na+) antiport (Figures 1 and 2). Drug efflux systems can be drug-/class-specific as for the original Tet pump and the more recently described Mef exporters of macrolides and various antimicrobial resistance. Bacterial efflux systems capable of accommodating antimicrobials generally fall into five classes, the major facilitator (MF) superfamily, the ATP-binding cassette (ABC) family, the resistance-nodulation-division (RND) family, the small multidrug resistance (SMR) family [a member of the much larger drug/metabolite transporter (DMT) superfamily] and the multidrug and toxic compound extrusion (MATE) family (see Reference 44 for an in-depth review of drug e (...truncated)