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Antimicrobial Agents and Chemotherapy, February 1998, p. 399-403, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

beta -Lactamase Inhibitors Are Substrates for the Multidrug Efflux Pumps of Pseudomonas aeruginosa

Xian-Zhi Li, Li Zhang, Ramakrishnan Srikumar, and Keith Poole*

Department of Microbiology and Immunology, Queen's University, Kingston, Ontario K7L 3N6, Canada

Received 10 June 1997/Returned for modification 9 October 1997/Accepted 1 December 1997

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.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Queen's University, Kingston, Ontario K7L 3N6, Canada. Phone: (613) 545-6677. Fax: 613-545-6796. E-mail: poolek{at}post.queensu.ca.

Antimicrobial Agents and Chemotherapy, February 1998, p. 399-403, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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