Multidrug Efflux Pumps and Their Inhibitors Characterized by Computational Modeling

Abstract

Antimicrobial resistance is a key public health concern of our era due to an ever-increasing number of drug-resistant pathogens, including several Gram- negative bacilli. The latter are endowed with a low permeable outer membrane and with numerous chromosomally encoded multidrug effl ux pumps, which are not only ubiquitous but also polyspecifi c, thus recognizing a broad range of compounds. Effl ux pumps are a major defense mechanism of these organisms against antimicro- bials as they can signifi cantly increase the levels of resistance by allowing time for the organisms to develop specifi c resistance mechanisms. One of the potential strate- gies to reinvigorate the effi cacy of antimicrobials is by joint administration with effl ux pump inhibitors, which either block the substrate binding and/or hinder any of the transport-dependent steps of the pumps. In this chapter, we provide an overview of multidrug resistance effl ux pumps, their inhibition strategies, and the important fi ndings from the various computational simulation studies reported to date with respect to the rational design of inhibitors and on deciphering their mechanism of action.