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Antimicrobial Agents and Chemotherapy, November 2005, p. 4608-4615, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4608-4615.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mechanisms of Azole Resistance in a Clinical Isolate of Candida tropicalis

Patrick Vandeputte,1* Gérald Larcher,1 Thierry Bergès,2 Gilles Renier,3 Dominique Chabasse,1 and Jean-Philippe Bouchara1

Groupe d'Etude des Interactions Hôte-Parasite, UPRES-EA 3142, Laboratoire de Parasitologie-Mycologie,1 Laboratoire d'Immunologie, Centre Hospitalier Universitaire, 49933 Angers Cedex 9,3 Laboratoire de Génétique de la Levure, CNRS UMR 6161, Faculté des Sciences, 86022 Poitiers Cedex, France2

Received 6 January 2005/ Returned for modification 1 July 2005/ Accepted 24 August 2005

Azole resistance has been insufficiently investigated in the yeast Candida tropicalis. Here we determined the molecular mechanisms responsible for azole resistance in a clinical isolate of this pathogenic yeast. Antifungal susceptibility testing performed by a disk diffusion method showed resistance or markedly decreased susceptibility to azoles, which was confirmed by determination of MICs. Considering the relationship between azole susceptibility and the respiration reported for other yeast species, the respiratory activity of this isolate was investigated. Flow cytometry using rhodamine 123 and oxygraphy demonstrated an increased respiratory activity, which was not linked to an overexpression or increased number of copies of the mitochondrial genome. Among previously described resistance mechanisms, an increased activity of efflux pumps was investigated by flow cytometry using rhodamine 6G. However, the efflux of rhodamine 6G was lower in the resistant isolate than in susceptible ones. Likewise, real-time reverse transcription-PCR quantification of the expression of C. tropicalis MDR1 (CtMDR1), which encodes an efflux protein belonging to the major facilitator superfamily, did not show overexpression of this gene. In contrast, the resistant isolate overexpressed the CtERG11 gene coding for lanosterol 14{alpha}-demethylase. This was in agreement with the larger amount of ergosterol found in this isolate. Moreover, sequencing of CtERG11 showed a point mutation leading to a tyrosine substitution in the protein sequence, which might lead to decreased binding affinity for azoles. In conclusion, overexpression of CtERG11 associated with a missense mutation in this gene seemed to be responsible for the acquired azole resistance of this clinical isolate.

* Corresponding author. Mailing address: Groupe d'Etude des Interactions Hôte-Parasite, UPRES-EA 3142, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, 4 rue Larrey, 49933 Angers Cedex 9, France. Phone: 33 02 41 35 34 72. Fax: 33 02 41 35 36 16. E-mail: Patrick.Vandeputte{at}etud.univ-angers.fr.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4608-4615, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4608-4615.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vandeputte, P., Tronchin, G., Rocher, F., Renier, G., Berges, T., Chabasse, D., Bouchara, J.-P. (2009). Hypersusceptibility to Azole Antifungals in a Clinical Isolate of Candida glabrata with Reduced Aerobic Growth. Antimicrob. Agents Chemother. 53: 3034-3041 [Abstract] [Full Text]  
  • Vandeputte, P., Tronchin, G., Larcher, G., Ernoult, E., Berges, T., Chabasse, D., Bouchara, J.-P. (2008). A Nonsense Mutation in the ERG6 Gene Leads to Reduced Susceptibility to Polyenes in a Clinical Isolate of Candida glabrata. Antimicrob. Agents Chemother. 52: 3701-3709 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J. (2007). Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem. Clin. Microbiol. Rev. 20: 133-163 [Abstract] [Full Text]  


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