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Antimicrobial Agents and Chemotherapy, March 2007, p. 1016-1021, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00704-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cumulative Effects of Several Nonenzymatic Mechanisms on the Resistance of Pseudomonas aeruginosa to Aminoglycosides{triangledown}

Farid El'Garch, Katy Jeannot, Didier Hocquet, Catherine Llanes-Barakat, and Patrick Plésiat*

Department of Bacteriology, University of Franche-Comté, Faculty of Medicine, F-25030 Besançon, France

Received 7 June 2006/ Returned for modification 14 August 2006/ Accepted 17 November 2006

Screening of a Tn5-Hg insertional library (12,000 clones) constructed in wild-type Pseudomonas aeruginosa strain PAO1 identified four genes (namely, galU, nuoG, mexZ, and rplY) whose disruption individually led to increased resistance to aminoglycosides (means of twofold). Inactivation of these genes was associated with (i) impaired outer membrane uptake, (ii) reduced active transport, (iii) increased MexXY-OprM-mediated active efflux, and (iv) alteration of target of aminoglycosides, respectively. In addition, suppression of the gene rplY, which codes for ribosomal protein L25, was found to result in both moderate upregulation of the efflux system MexXY-OprM and hypersusceptibility to ß-lactam antibiotics. Construction of double, triple, and quadruple mutants demonstrated cumulative effects of the different mechanisms on aminoglycoside resistance, with MICs increasing from 16- to 64-fold in the quadruple mutant compared to the wild-type strain PAO1. Altogether, these results illustrate how P. aeruginosa may gradually develop high resistance to these antibiotics via intrinsic (i.e., nonenzymatic) mechanisms, as in cystic fibrosis patients.

* Corresponding author. Mailing address: Laboratoire de Bactériologie, UFR Sciences Médicales et Pharmaceutiques, 19 Rue Ambroise Paré, 25041 Besançon Cedex 3, France. Phone: (33) 3 81 66 82 86. Fax: (33) 3 81 66 89 14. E-mail: patrick.plesiat{at}univ-fcomte.fr.

{triangledown} Published ahead of print on 28 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 1016-1021, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00704-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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