Multidrug resistance protein MexD and Multidrug resistance protein MexY (MexD and MexY)

MexD and MexY are essential inner membrane transporter proteins belonging to the Resistance-Nodulation-Division (RND) family in the opportunistic pathogen Pseudomonas aeruginosa. They serve as the substrate-binding and energy-coupling components of the MexCD-OprJ and MexXY-OprM tripartite efflux systems, respectively (UniProt P52478, O30771). These systems utilize the proton motive force to actively extrude a diverse array of antimicrobial agents, including aminoglycosides, fluoroquinolones, and macrolides, from the cytoplasm and periplasm directly into the external environment (PubMed 22252813). MexY is particularly notable as the primary determinant of aminoglycoside resistance in clinical isolates, while MexD contributes significantly to resistance against newer fluoroquinolones and detergents (PubMed 8655562). Because these pumps are major drivers of the multidrug-resistant (MDR) phenotype in P. aeruginosa, they are prime targets for the development of efflux pump inhibitors (EPIs). Successfully inhibiting MexD and MexY could potentially reverse antibiotic resistance and enhance the efficacy of existing clinical treatments for severe infections, such as those found in cystic fibrosis patients (PubMed 11159622).

Other names

MexCD-OprJ efflux systemMexXY-OprM efflux systemRND-family multidrug efflux pumpsMexDMexY

Efflux pump inhibitors (EPIs) target MexD and MexY by binding to their substrate-binding pockets, which competitively or non-competitively blocks the extrusion of antibiotics. This inhibition increases the intracellular concentration of drugs, thereby restoring the efficacy of antibiotics that would otherwise be pumped out of the bacterial cell.