Impact of Antimicrobial Drug Efflux Pumps on Antimicrobial Discovery and Development

Antimicrobial efflux pumps reduce intracellular drug levels and play important roles in intrinsic and acquired drug resistance in bacteria. Their impact on antimicrobial discovery and development is multifaceted. Bacterial strains deficient in drug efflux can be used in cell-based assays (including high-throughput screening) to facilitate identification of antibacterial candidates. Drug efflux pump components and their expressional regulatory pathways are potential targets for antimicrobial discovery; these targets can be exploited for the development of drug efflux pump inhibitors to be administered as antimicrobial adjuvants in antimicrobial combination therapy. Although the scientific boom within the current “omics” era has increasingly identified numerous novel drug targets, many newly developed antimicrobials are mainly against Gram-positive bacteria, and their activities are hindered by promiscuous multidrug efflux pumps and the membrane permeability barrier of Gram-negative pathogens. Bypassing this efflux action and improving drug penetration provide important strategies for rational drug design which require careful consideration of both antimicrobial physicochemical properties and the features of drug efflux pumps/membrane barrier. This chapter describes the various impacts of drug efflux pumps on antimicrobial discovery and development.