Structure-Based Drug Design Targeting the Substrate-Binding Pocket of MexB

The multidrug-resistant (MDR) phenotype of Pseudomonas aeruginosa poses a significant clinical challenge and frequently causes severe and potentially lethal infections. The activity of efflux proteins, which are membrane transporters that use the electrochemical gradient across the bacterial membrane to extrude antimicrobials and reduce their intracellular concentrations, is a significant factor in this resistance. One of the most well-known mechanisms of multidrug resistance in Pseudomonas aeruginosa is the Resistance-Nodulation-Division (RND) efflux pump system. MexB, the inner membrane transporter, is essential for substrate recognition and drug binding in the well-characterised MexAB-OprM complex. A variety of antibiotics, such as Macrolides, Fluoroquinolones, Tetracyclines, Sulfonamides, β-Lactams, Trimethoprim, Novobiocin, and Chloramphenicol, are resistant to this pump. The overexpression of this tripartite efflux system, which consists of the outer membrane channel OprM, the membrane fusion protein MexA, and the inner membrane transporter MexB, is regulated by genes including mexR, nalC, and nalD. MexB involvement in drug resistance makes it a prime target for the development of efflux pump inhibitors (EPIs). Antibiotics and EPIs together have the potential to restore antibacterial activity by enhancing intracellular drug retention. However, restricted access to complex structural and computational tools required for logical drug design has hindered the development of EPI. This study examines novel EPIs that target P. aeruginosa RND-type efflux systems and discusses recent structural discoveries regarding the MexB transporter.