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Antimicrobial Agents and Chemotherapy, November 2005, p. 4733-4738, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4733-4738.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Molecular Mechanisms of ß-Lactam Resistance Mediated by AmpC Hyperproduction in Pseudomonas aeruginosa Clinical Strains

Carlos Juan,1 María D. Maciá,1 Olivia Gutiérrez,1 Carmen Vidal,2 José L. Pérez,1 and Antonio Oliver1*

Servicio de Microbiología,1 Unidad de Secuenciación, Hospital Son Dureta, Palma de Mallorca, Spain2

Received 3 May 2005/ Returned for modification 11 August 2005/ Accepted 13 August 2005

The molecular mechanisms of ß-lactam resistance mediated by AmpC hyperproduction in natural strains of Pseudomonas aeruginosa were investigated in a collection of 10 isogenic, ceftazidime-susceptible and -resistant pairs of isolates, each sequentially recovered from a different intensive care unit patient treated with ß-lactams. All 10 ceftazidime-resistant mutants hyperproduced AmpC (ß-lactamase activities were 12- to 657-fold higher than those of the parent strains), but none of them harbored mutations in ampR or the ampC-ampR intergenic region. On the other hand, six of them harbored inactivating mutations in ampD: four contained frameshift mutations, one had a C->T mutation, creating a premature stop codon, and finally, one had a large deletion, including the complete ampDE region. Complementation studies revealed that only three of the six ampD mutants could be fully transcomplemented with either ampD- or ampDE-harboring plasmids, whereas one of them could be transcomplemented only with ampDE and two of them (including the mutant with the deletion of the ampDE region and one with an ampD frameshift mutation leading to an ampDE-fused open reading frame) could not be fully transcomplemented with any of the plasmids. Finally, one of the four mutants with no mutations in ampD could be transcomplemented, but only with ampDE. Although the inactivation of AmpD is found to be the most frequent mechanism of AmpC hyperproduction in clinical strains, our findings suggest that for certain types of mutations, AmpE plays an indirect role in resistance and that there are other unknown genes involved in AmpC hyperproduction, with at least one of them apparently located close to the ampDE operon.

* Corresponding author. Mailing address: Servicio de Microbiología, Hospital Son Dureta, C. Andrea Doria No. 55, 07014 Palma de Mallorca, Spain. Phone: 34 971 175 185. Fax: 34 971 175 185. E-mail: aoliver{at}hsd.es.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4733-4738, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4733-4738.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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