Towards understanding promiscuity in multidrug efflux pumps

• Multidrug transporters cause failure of antibacterial and cancer chemotherapy.
• Inhibition of these pumps is a target for therapeutic intervention.
• Molecular explanations for multidrug resistance (MDR) pump promiscuity are required.
• Structures of these pumps are enabling insights into their mechanisms.
• Development of inhibitors using these structural advances is a genuine possibility.

Drug export from cells is a major factor in the acquisition of cellular resistance to antimicrobial and cancer chemotherapy, and poses a significant threat to future clinical management of disease. Many of the proteins that catalyse drug efflux do so with remarkably low substrate specificity, a phenomenon known as multidrug transport. For these reasons we need a greater understanding of drug recognition and transport in multidrug pumps to inform research that attempts to circumvent their action. Structural and computational studies have been heralded as being great strides towards a full elucidation of multidrug recognition and transport. In this review we summarise these advances and ask how close we are to a molecular understanding of this remarkable phenomenon.