This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Epp, S. F.
Right arrow Articles by Pechère, J.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Epp, S. F.
Right arrow Articles by Pechère, J.-C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2001, p. 1780-1787, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1780-1787.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

C-Terminal Region of Pseudomonas aeruginosa Outer Membrane Porin OprD Modulates Susceptibility to Meropenem

Simone F. Epp,1 Thilo Köhler,1,* Patrick Plésiat,2 Mehri Michéa-Hamzehpour,1 Joachim Frey,3 and Jean-Claude Pechère1

Département de Génétique et Microbiologie, Centre Médical Universitaire, 1211 Geneva 4,1 and Institut für Veterinär-Bakteriologie, Forschungsabteilung, Universität Bern, 3012 Bern,3 Switzerland, and Laboratoire de Bactériologie, Hôpital Minjoz, F-25000 Besançon, France2

Received 18 September 2000/Returned for modification 15 January 2001/Accepted 2 March 2001

We investigated the unusual susceptibility to meropenem observed for seven imipenem-resistant clinical isolates of Pseudomonas aeruginosa. These strains were genetically closely related, expressed OprD, as determined by Western blot analyses, and were resistant to imipenem (>5 µg/ml) but susceptible to meropenem (<1 µg/ml). The oprD genes from two isolates were entirely sequenced, and their deduced protein sequences showed 93% identity with that of OprD of strain PAO1. The major alteration consisted of the replacement of a stretch of 12 amino acids, located in putative external loop L7 of OprD, by a divergent sequence of 10 amino acid residues. The oprD gene variants and the wild-type oprD gene were cloned and expressed in a defined oprD mutant. The meropenem MICs for strains carrying the oprD genes from clinical isolates were four times lower than that for the strain carrying the wild-type oprD gene. Imipenem activities, however, were comparable for all strains. Furthermore, meropenem hypersusceptibility was obtained with a hybrid OprD porin that consisted of the PAO1 oprD gene containing loop L7 from a clinical isolate. These results show that the C-terminal portion of OprD, in particular, loop L7, was responsible for the unusual meropenem hypersusceptibility. Competition experiments suggested that the observed OprD modifications in the clinical isolates did not affect antagonism between imipenem and the basic amino acid L-lysine. We further propose that shortening of putative loop L7 of the OprD porin by 2 amino acid residues sufficiently opens the porin channel to allow optimal penetration of meropenem and increase its activity. In contrast, this alteration would not affect susceptibility to a smaller carbapenem molecule, such as imipenem.

* Corresponding author. Mailing address: Department of Genetics and Microbiology, CMU, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. Phone: 41-22-7025655. Fax: 41-22-7025702. E-mail: Thilo.Kohler{at}medecine.unige.ch.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1780-1787, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1780-1787.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Rodriguez-Martinez, J.-M., Poirel, L., Nordmann, P. (2009). Molecular Epidemiology and Mechanisms of Carbapenem Resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 53: 4783-4788 [Abstract] [Full Text]  
  • Reinhardt, A., Kohler, T., Wood, P., Rohner, P., Dumas, J.-L., Ricou, B., van Delden, C. (2007). Development and Persistence of Antimicrobial Resistance in Pseudomonas aeruginosa: a Longitudinal Observation in Mechanically Ventilated Patients. Antimicrob. Agents Chemother. 51: 1341-1350 [Abstract] [Full Text]  
  • Siempos, I. I., Vardakas, K. Z., Manta, K. G., Falagas, M. E. (2007). Carbapenems for the treatment of immunocompetent adult patients with nosocomial pneumonia. Eur Respir J 29: 548-560 [Abstract] [Full Text]  
  • (2005). Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia. Am. J. Respir. Crit. Care Med. 171: 388-416 [Full Text]  
  • Perron, K., Caille, O., Rossier, C., van Delden, C., Dumas, J.-L., Kohler, T. (2004). CzcR-CzcS, a Two-component System Involved in Heavy Metal and Carbapenem Resistance in Pseudomonas aeruginosa. J. Biol. Chem. 279: 8761-8768 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»