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Antimicrobial Agents and Chemotherapy, March 2007, p. 982-990, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01510-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Reduced Susceptibility to Polyenes Associated with a Missense Mutation in the ERG6 Gene in a Clinical Isolate of Candida glabrata with Pseudohyphal Growth

Groupe d'Etude des Interactions Hôte-Parasite, UPRES-EA 3142, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, 49933 Angers Cedex 9,¹ Laboratoire de Génétique de la Levure, CNRS UMR 6161, Faculté des Sciences, 86022 Poitiers Cedex,² Laboratoire de Parasitologie-Mycologie, Hôpital Tenon, 75970 Paris Cedex 20, France³

Received 30 November 2006/ Accepted 2 December 2006

Little information is available about the molecular mechanisms responsible for polyene resistance in pathogenic yeasts. A clinical isolate of Candida glabrata with a poor susceptibility to polyenes, as determined by disk diffusion method and confirmed by determination of MIC, was recovered from a patient treated with amphotericin B. Quantitative analysis of sterols revealed a lack of ergosterol and an accumulation of late sterol intermediates, suggesting a defect in the final steps of the ergosterol pathway. Sequencing of CgERG11, CgERG6, CgERG5, and CgERG4 genes revealed exclusively a unique missense mutation in CgERG6 leading to the substitution of a cysteine by a phenylalanine in the corresponding protein. In addition, real-time reverse transcription-PCR demonstrated an overexpression of genes encoding enzymes involved in late steps of the ergosterol pathway. Moreover, this isolate exhibited a pseudohyphal growth whatever the culture medium used, and ultrastructural changes of the cell wall of blastoconidia were seen consisting in a thinner inner layer. Cell wall alterations were also suggested by the higher susceptibility of growing cells to Calcofluor white. Additionally, complementation of this isolate with a wild-type copy of the CgERG6 gene restored susceptibility to polyenes and a classical morphology. Together, these results demonstrated that mutation in the CgERG6 gene may lead to a reduced susceptibility to polyenes and to a pseudohyphal growth due to the subsequent changes in sterol content of the plasma membrane.

Published ahead of print on 11 December 2006.

This article has been cited by other articles:

• 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]