title: Beta-lactamase inhibitors are substrates for the multidrug efflux pumps of Pseudomonas aeruginosa.
abstract: The MexAB-OprM multidrug efflux system exports a number of antimicrobial compounds, including beta-lactams. In an attempt to define more fully the range of antimicrobial compounds exported by this system, and, in particular, to determine whether beta-lactamase inhibitors were also accommodated by the MexAB-OprM pump, the influence of pump status (its presence or absence) on the intrinsic antibacterial activities of these compounds and on their abilities to enhance beta-lactam susceptibility in intact cells was assessed. MIC determinations clearly demonstrated that all three compounds tested, clavulanate, cloxacillin, and BRL42715, were accommodated by the pump. Moreover, by using beta-lactams which were readily hydrolyzed by the Pseudomonas aeruginosa class C chromosomal beta-lactamase, it was demonstrated that elimination of the mexAB-oprM-encoded efflux system greatly enhanced the abilities of cloxacillin and BRL42715 (but not clavulanate) to increase beta-lactam susceptibility. With beta-lactams which were poorly hydrolyzed, however, the inhibitors failed to enhance beta-lactam susceptibility in MexAB-OprM+ strains, although BRL42715 did enhance beta-lactam susceptibility in MexAB-OprM- strains, suggesting that even with poorly hydrolyzed beta-lactams this inhibitor was effective when it was not subjected to efflux. MexEF-OprN-overexpressing strains, but not MexCD-OprJ-overexpressing strains, also facilitated resistance to beta-lactamase inhibitors, indicating that these compounds are also substrates for the MexEF-OprN pump. These data indicate that an ability to inactivate MexAB-OprM (and like efflux systems in other bacteria) will markedly enhance the efficacies of beta-lactam-beta-lactamase inhibitor combinations in treating bacterial infections.
authors.affiliation: Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada.
authors.forename: X Z
authors.initials: XZ
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Srikumar
authors.forename: K
authors.initials: K
authors.lastname: Poole
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000187:drug effects; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases