Efflux-mediated drug resistance in bacteria: an update

Abstract

Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome, although they can also be plasmid-encoded. A previous article in this journal provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past 5 years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria.

Fig. 1

Crystal structures of multidrug efflux transporters exemplified by AcrAB-TolC[55, 107, 119] and EmrD[70] of E. coli and Sav1866 of S. aureus.[56] Instead of AcrA, we show the recent complete structure of its homologue MexA.[108] See text and the relevant references for details of the structural properties of these transporters. The figures were drawn by Pymol (http://www.pymol.org) by using the coordinate files 2DRD (AcrB), 2V4D (MexA), 2VDE (TolC, an open form), 2GFP (EmrD), and 2HYD (Sav1866), obtained from the Protein Data Bank. The models were colored in rainbow colors (N-terminus blue, C-terminus red) and the approximate positions of membrane bilayers are indicated by horizontal lines. Note that for oligomeric proteins, the rainbow color was selected from the N-terminus of one protomer all the way to the C-terminus of another protomer. Proteins were positioned so that the external portion is up in the figure. The bound minocycline in the AcrB structure is shown in red rods (highlighted by a green arrow).

Fig. 2

Regulation of the RND superfamily Mex transporters of P. aeruginosa. The efflux systems are shown in the light blue blocks with the respective transcriptional units presented in the solid grey lines. All regulators are shown in the green boxes, and their functions as repressor or activator are indicated, respectively, in the green or orange dotted arrows. The inverse relationship between MexAB-OprM expression and MexCD-OprJ/MexEF-OprN expression is marked by a double arrowed line. Interaction of the regulators (MexR or MexT) with the modulators (ArmR or MexT) is denoted by the double arrowed dotted lines. See text and relevant references for details of the regulation. MDA=membrane-damaging agents; QS AIs= quorum-sensing autoinducers.

Fig. 3

Regulation of multidrug or drug-specific efflux transporters of S. aureus. The efflux transporters are shown in colour blocks. All regulators are presented in the green boxes, and their functions as repressor or activator are indicated, respectively, by the green or orange dotted arrows. Unknown regulators are marked with a question mark (?) with the dotted grey lines linked to the relevant transporters. See text and relevant references for details of the regulation.