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Antimicrobial Agents and Chemotherapy, December 1999, p. 2975-2983, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Characterization of a Pseudomonas aeruginosa Efflux Pump Contributing to Aminoglycoside Impermeability

Shannon Westbrock-Wadman, David R. Sherman,dagger Mark J. Hickey, Silvija N. Coulter, Ya Qi Zhu, Paul Warrener, Lisa Y. Nguyen, Ribhi M. Shawar, Kim R. Folger, and C. Kendall Stover*

PathoGenesis Corporation, Seattle, Washington 98119

Received 11 May 1999/Returned for modification 1 June 1999/Accepted 30 September 1999

Pseudomonas aeruginosa can employ many distinct mechanisms of resistance to aminoglycoside antibiotics; however, in cystic fibrosis patients, more than 90% of aminoglycoside-resistant P. aeruginosa isolates are of the impermeability phenotype. The precise molecular mechanisms that produce aminoglycoside impermeability-type resistance are yet to be elucidated. A subtractive hybridization technique was used to reveal gene expression differences between PAO1 and isogenic, spontaneous aminoglycoside-resistant mutants of the impermeability phenotype. Among the many genes found to be up-regulated in these laboratory mutants were the amrAB genes encoding a recently discovered efflux system. The amrAB genes appear to be the same as the recently described mexXY genes; however, the resistance profile that we see in P. aeruginosa is very different from that described for Escherichia coli with mexXY. Direct evidence for AmrAB involvement in aminoglycoside resistance was provided by the deletion of amrB in the PAO1-derived laboratory mutant, which resulted in the restoration of aminoglycoside sensitivity to a level nearly identical to that of the parent strain. Furthermore, transcription of the amrAB genes was shown to be up-regulated in P. aeruginosa clinical isolates displaying the impermeability phenotype compared to a genotypically matched sensitive clinical isolate from the same patient. This suggests the possibility that AmrAB-mediated efflux is a clinically relevant mechanism of aminoglycoside resistance. Although it is unlikely that hyperexpression of AmrAB is the sole mechanism conferring the impermeability phenotype, we believe that the Amr efflux system can contribute to a complex interaction of molecular events resulting in the aminoglycoside impermeability-type resistance phenotype.

* Corresponding author. Mailing address: PathoGenesis Corporation, 201 Elliott Ave. W., Seattle, WA 98119. Phone: (206) 270-3309. Fax: (206) 282-5065. E-mail: kstover{at}pathogenesis.com.

dagger Present address: Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195.

Antimicrobial Agents and Chemotherapy, December 1999, p. 2975-2983, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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