Multidrug resistance protein MexD and Multidrug resistance protein MexY efflux pump systems (MexD/MexY)

The Multidrug resistance protein MexD (part of the MexCD-OprJ system) and Multidrug resistance protein MexY (part of the MexXY-OprM system) are critical Resistance-Nodulation-Division (RND) family efflux pumps in the opportunistic pathogen Pseudomonas aeruginosa (Morita et al., 2012; Poole et al., 1996). These tripartite complexes span the inner and outer membranes, utilizing the proton motive force to actively expel a wide range of antibiotics, including fluoroquinolones, macrolides, and aminoglycosides, before they reach their intracellular targets (Li et al., 2015). MexXY-OprM is particularly notable as the primary mechanism for aminoglycoside resistance in clinical isolates, while MexCD-OprJ is often upregulated in response to biocides and specific environmental stresses (Morita et al., 2012). Overexpression of these pumps, frequently driven by mutations in regulatory genes like mexZ or nfxB, significantly contributes to the multidrug-resistant (MDR) phenotype of P. aeruginosa in cystic fibrosis and hospital-acquired infections (Lomovskaya et al., 2001). Consequently, these systems are major targets for the development of efflux pump inhibitors (EPIs) intended to restore antibiotic susceptibility (Lomovskaya et al., 2001). While several experimental inhibitors have been identified, clinical application remains challenging due to potential toxicity and the complex regulatory network of the bacteria (Li et al., 2015).

Other names

MexDMexYMexCD-OprJMexXY-OprMMexXY-OprARND-type efflux pumpsResistance-Nodulation-Division transporters

These systems function as tripartite pumps that actively extrude antibiotics from the periplasm or cytoplasm to the external environment, driven by the proton motive force. Drugs targeting these systems (efflux pump inhibitors) act by competitively or non-competitively inhibiting the transporter subunits (MexD or MexY), thereby restoring the intracellular concentration and efficacy of co-administered antibiotics.