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Review
, 19 (2), 382-402

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

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Review

Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

Laura J V Piddock. Clin Microbiol Rev.

Abstract

Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed.

Figures

FIG. 1.
FIG. 1.
Diagrammatic comparison of the five families of efflux pumps. (Courtesy of Melissa Brown; reproduced by kind permission.)
FIG. 2.
FIG. 2.
Comparison of the genetic organization of E. coli acrRAB with S. enterica serovar Typhimurium acrRAB, C. jejuni cmeABC, and P. aeruginosa mexAB-OprM. This diagram shows the similarities between the RND MDR efflux pump genes of different bacterial species.
FIG. 3.
FIG. 3.
Model of the assembled tripartite drug efflux pump. This possible model of an RND-class drug efflux pump is based on the open-state model of TolC (red) forming a minimal contact interface with the six hairpins at the apex of AcrB (green). A ring of nine MexA molecules (blue) is modeled to form a sheath around AcrB and the α-barrel of TolC (MexA is a close homologue of AcrA, the natural partner of AcrB/TolC). Variants of the model might include a lower-order oligomer of MexA (4) and more extensive interaction between AcrB and TolC. IM, inner membrane; OM, outer membrane. (Reprinted from reference with permission from Elsevier and V. Koronakis.)

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