Antimicrobial Drug Efflux Pump Inhibitors

Abstract

Bacterial multidrug resistance is on the rise, and bacterial efflux pumps make a major contributor to this development. Efflux pump inhibitors (EPIs) may be a solution to this problem, since they can reverse resistance to clinically administered antimicrobial agents. Multiple EPIs with activity against Gram-positive and Gram-negative bacteria have been described over the past decades. However, none of the synthetic EPIs have currently reached a stage of clinical applicability. Investigators have evaluated certain drugs already in clinical use for their ability to potentiate the activity of antimicrobials via inhibition of drug efflux pumps. Most of the compounds reported to date do not reach clinical concentrations for EPI activity at the in vivo target site, with a notable exception, i.e., thioridazine shown to potentiate the killing of Mycobacterium tuberculosis in human macrophages. Our understanding of the molecular mechanisms for efflux pump inhibition has been considerably advanced, mainly because of the availability of crystal structures of multidrug transporters, including those in complex with substrates or EPIs (in particular with the AcrAB-TolC efflux system of Escherichia coli). Crystallographic data as well as results from mutagenesis and computational chemistry studies have laid the foundation for rational EPI design.