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Antimicrobial Agents and Chemotherapy, July 2001, p. 2001-2007, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2001-2007.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

MexXY-OprM Efflux Pump Is Required for Antagonism of Aminoglycosides by Divalent Cations in Pseudomonas aeruginosa

Weimin Mao, Mark S. Warren, Angela Lee, Anita Mistry, and Olga Lomovskaya*

Microcide Pharmaceuticals Inc., Mountain View, California 94043

Received 20 October 2000/Returned for modification 8 March 2001/Accepted 21 April 2001

Antagonism of aminoglycosides by divalent cations is well documented for Pseudomonas aeruginosa and is regarded as one of the problems in aminoglycoside therapy. It is generally considered that divalent cations interfere with uptake of aminoglycosides at both the outer and inner membranes. It has been demonstrated recently that aminoglycosides can be removed from cells of P. aeruginosa by the three-component multidrug resistance efflux pump MexXY-OprM. We sought to investigate the interplay between efflux and uptake in resistance to aminoglycosides in P. aeruginosa. To do so, we studied the effects of the divalent cations Mg2+ and Ca2+ on susceptibility to aminoglycosides in a wild-type strain of P. aeruginosa and in mutants either overexpressing or lacking the MexXY-OprM efflux pump. MICs of gentamicin, streptomycin, amikacin, apramycin, netilmicin, and arbekacin were determined in Mueller-Hinton broth in the presence of cations added at concentrations that varied from 0.125 to 8 mM. We found, unexpectedly, that while both Mg2+ and Ca2+ antagonized aminoglycosides (up to a 64-fold decrease in susceptibility at 8 mM), antagonism was seen only in the strains of P. aeruginosa that contained the functional MexXY-OprM efflux pump. Our results indicate that inhibition of the MexXY-OprM efflux pump should abolish the antagonism of aminoglycosides by divalent cations, regardless of its precise mechanism. This may significantly increase the therapeutic index of aminoglycosides and improve the clinical utility of this important class of antibiotics.

* Corresponding author. Mailing address: Microcide Pharmaceuticals Inc., 850 Maude Ave., Mountain View, CA 94043. Phone: (650) 428-3548. Fax: (650) 428-3550. E-mail: olga{at}microcide.com.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2001-2007, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2001-2007.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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