MexXY-OprM multidrug efflux pump complex (MexXY-OprM)

The MexXY-OprM multidrug efflux pump complex is a tripartite Resistance-Nodulation-Division (RND) transporter in Pseudomonas aeruginosa, comprising the inner membrane antiporter MexY, periplasmic fusion protein MexX, and outer membrane channel OprM (often borrowed from the MexAB-OprM operon). It extrudes a broad range of substrates, notably aminoglycosides like gentamicin and amikacin that other pumps like MexAB-OprM cannot handle, as well as fluoroquinolones, macrolides, tetracyclines, chloramphenicol, spectinomycin, and cefepime, using proton motive force to drive peristaltic conformational changes (loose-tight-open states) for substrate transport from the periplasm or inner leaflet directly to the exterior. MexY forms a homotrimer with a proton relay network in transmembrane helices and substrate-binding sites in its periplasmic cleft, including flexible F- and G-loops, with charged residues like D133, K173, D615, and E644 contributing to its distinct specificity compared to homologs like AcrB or MexB. Expression is tightly regulated, not constitutive, involving repression by MexZ (antagonized by ArmZ under ribosome stress or antibiotic induction), and activation via two-component systems like ParRS, AmgRS, and PmrAB in response to antibiotics, cationic peptides, or membrane stress. Upregulation, often via MexZ mutations or regulators like ArmZ, drives clinical aminoglycoside resistance in P. aeruginosa isolates from cystic fibrosis, nosocomial pneumonia, sepsis, and wounds, contributing to over 300,000 global antimicrobial-resistant deaths annually. As a key resistance determinant without approved direct inhibitors, it poses therapeutic challenges but represents a target for efflux pump inhibitors to potentiate antibiotics.

Other names

MexXY pumpMexXY efflux system

Efflux pump inhibition (to restore antibiotic efficacy), Substrate extrusion via peristaltic motion through loose-tight-open conformational cycling, Proton translocation for energy coupling