MDR Efflux Pumps: Structure and Regulation

Abstract

Multidrug resistance (MDR) represents a major challenge in the treatment of bacterial infections and cancer chemotherapy. A key contributor to MDR is the activity of efflux pumps, which are membrane transport proteins capable of extruding a wide variety of structurally unrelated compounds out of the cell. These efflux systems decrease the intracellular concentration of antimicrobial agents, thereby reducing their efficacy. Based on their structure and energy sources, efflux pumps are classified into several families, including the ATP-binding cassette (ABC), major facilitator superfamily (MFS), resistance-nodulation-division (RND), multidrug and toxic compound extrusion (MATE), and small multidrug resistance (SMR) families. The regulation of efflux pumps involves complex genetic and environmental controls. Global transcriptional regulators, two-component systems, and local repressors or activators tightly modulate efflux pump expression in response to environmental stresses, drug exposure, or metabolic needs. Overexpression of these pumps not only contributes to antibiotic resistance in bacteria but also influences biofilm formation, virulence, and cell survival under stress conditions. Understanding the structural basis and regulatory mechanisms of efflux pumps is crucial for developing inhibitors that can restore drug susceptibility. Efflux pump inhibitors (EPIs), either natural or synthetic, are being investigated as adjuvant therapies to combat MDR pathogens and improve treatment outcomes.