Substrate Specificities of MexAB-OprM, MexCD-OprJ, and MexXY-OprM Efflux Pumps in <i>Pseudomonas aeruginosa</i>

TLDR

The study aims to determine the exact substrate specificities of the MexAB‑OprM, MexCD‑OprJ, and MexXY‑OprM efflux pumps in *Pseudomonas aeruginosa*. This was accomplished by generating isogenic mutants that overproduce one pump while lacking the other two, as well as mutants lacking all three pumps. The pumps extrude a wide array of antimicrobials—including quinolones, macrolides, tetracyclines, lincomycin, chloramphenicol, most penicillins, most cephems, meropenem, and S‑4661—but not polymyxin B or imipenem; MexXY‑OprM uniquely extrudes aminoglycosides, MexAB‑OprM uniquely extrudes certain β‑lactams (carbenicillin, sulbenicillin, ceftazidime, moxalactam, aztreonam), and MexAB‑OprM and MexCD‑OprJ extrude novobiocin, cefsulodin, and flomoxef while MexXY‑OprM does not, revealing distinct substrate profiles from prior reports.

Abstract

ABSTRACT To find the exact substrate specificities of three species of tripartite efflux systems of Pseudomonas aeruginosa , MexAB-OprM, MexCD-OprJ, and MexXY-OprM, we constructed a series of isogenic mutants, each of which constitutively overproduced one of the three efflux systems and lacked the other two, and their isogenic mutants, which lacked all these systems. Comparison of the susceptibilities of the constructed mutants to 52 antimicrobial agents belonging to various groups suggested the following substrate specificities. All of the efflux systems extrude a wide variety of antimicrobial agent groups, i.e., quinolones, macrolides, tetracyclines, lincomycin, chloramphenicol, most penicillins (all but carbenicillin and sulbenicillin), most cephems (all but cefsulodin and ceftazidime), meropenem, and S-4661, but none of them extrude polymyxin B or imipenem. Extrusion of aminoglycosides is specific to MexXY-OprM, and extrusion of a group of the β-lactams, i.e., carbenicillin, sulbenicillin, ceftazidime, moxalactam, and aztreonam, is specific to MexAB-OprM. Moreover, MexAB-OprM and MexCD-OprJ extrude novobiocin, cefsulodin, and flomoxef, while MexXY-OprM does not. These substrate specificities are distinct from those reported previously.