Mycobacterial efflux pump (MEP)

Mycobacterial efflux pumps are a diverse group of transmembrane transport proteins in Mycobacterium tuberculosis and other mycobacteria that actively extrude a wide array of substrates, including clinically vital anti-tubercular drugs. These pumps are classified into five major superfamilies: ATP-binding cassette (ABC), Major Facilitator Superfamily (MFS), Resistance-Nodulation-Division (RND), Small Multidrug Resistance (SMR), and Multidrug and Toxic Compound Extrusion (MATE). They serve as primary mechanisms of both intrinsic and acquired drug resistance by lowering the intracellular concentration of antibiotics such as isoniazid, rifampicin, and fluoroquinolones to sub-lethal levels, which often facilitates the subsequent development of high-level chromosomal resistance. Beyond their role in drug resistance, specific pumps like MmpL3 are essential for the translocation of trehalose monomycolate across the inner membrane for cell wall synthesis, while others contribute to bacterial virulence and survival within host macrophages. Targeting these pumps with efflux pump inhibitors is a promising strategy to restore antibiotic susceptibility and shorten the duration of tuberculosis treatment.

Other names

Mycobacterial multidrug efflux pumpMycobacterial efflux systemDrug efflux transporterEfflux proteinMycobacterial membrane protein Large 3 (MmpL3)Rv1258c (Tap)EfpARv0194

Efflux pump inhibitors (EPIs) function by directly binding to and blocking the substrate binding site or exit channel, competing with antibiotics for transport, or dissipating the proton motive force (PMF) and ATP levels required for active transport.