Carbapenem activities against Pseudomonas aeruginosa: respective contributions of OprD and efflux systems

Abstract

While meropenem MICs were strongly influenced by the presence or absence of the MexAB-OprM efflux pump in both OprD-proficient and -deficient strain backgrounds, MICs of imipenem and of ER-35786 remained unchanged, demonstrating that meropenem is a substrate of MexAB-OprM but not imipenem and ER-35786. In vitro, all three carbapenems selected loss of OprD as a first mechanism of resistance. However, in an OprD-deficient background, meropenem was able to select MexAB-OprM overproducers as a secondary resistance mechanism, while ER-35786 selected a mutant cross-resistant to sparfloxacin and cefpirome.

FIG. 1

Chemical structures of the three carbapenems studied. Arrowheads indicate nitrogen atoms which can be charged positively.

FIG. 2

(A) Outer membrane preparations of defined and spontaneous PAO1 derived mutants. Lane 1, PAO1; lane 2, PASE1; lane 3, PA1433; lane 4, PA1436; lane 5, PA1434; lane 6, PA1423. Arrows indicate reduced expression of 55-kDa protein (lanes 3, 4) and presence of OprM (lane 5) and OprD (lane 6). (B) Western blots of total cell lysates obtained from the same strains as in panel A. The blots were revealed with anti-OprM antibody by using a chemiluminescent detection kit.