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Antimicrobial Agents and Chemotherapy, August 2003, p. 2404-2412, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2404-2412.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents

Dominique Sanglard,1* Françoise Ischer,1 Tania Parkinson,2 Derek Falconer,2 and Jacques Bille1

University Hospital Lausanne (CHUV), CH-1011 Lausanne, Switzerland,1 Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom2

Received 14 February 2003/ Returned for modification 8 April 2003/ Accepted 5 May 2003

The role of sterol mutations in the resistance of Candida albicans to antifungal agents has not been thoroughly investigated. Previous work reported that clinical C. albicans strains resistant to both azole antifungals and amphotericin B were defective in ERG3, a gene encoding sterol {Delta}5,6-desaturase. It is also believed that a deletion of the lanosterol 14{alpha}-demethylase gene, ERG11, is possible only under aerobic conditions when ERG3 is not functional. We tested these hypotheses by creating mutants by targeted deletion of the ERG3 and ERG11 genes and subjecting those mutants to antifungal susceptibility testing and sterol analysis. The homozygous erg3/erg3 mutant created, DSY1751, was resistant to azole derivatives, as expected. This mutant was, however, slightly more susceptible to amphotericin B than the parent wild type. It was possible to generate erg11/erg11 mutants in the DSY1751 background but also, surprisingly, in the background of a wild-type isolate with functional ERG3 alleles under aerobic conditions. This mutant (DSY1769) was obtained by exposure of an ERG11/erg11 heterozygous strain in a medium containing 10 µg of amphotericin B per ml. Amphotericin B-resistant strains were obtained only from ERG11/erg11 heterozygotes at a frequency of approximately 5 x 10-5 to 7 x 10-5, which was consistent with mitotic recombination between the first disrupted erg11 allele and the other remaining functional ERG11 allele. DSY1769 was also resistant to azole derivatives. The main sterol fraction in DSY1769 contained lanosterol and eburicol. These studies showed that erg11/erg11 mutants of a C. albicans strain harboring a defective erg11 allele can be obtained in vitro in the presence of amphotericin B. Amphotericin B-resistant strains could therefore be selected by similar mechanisms during antifungal therapy.

* Corresponding author. Mailing address: Institute of Microbiology, University Hospital Lausanne, Rue de Bugnon 44, CH-1011 Lausanne, Switzerland. Phone: 41 21 3144083. Fax: 41 21 3144060. E-mail: Dominique.Sanglard{at}chuv.hospvd.ch.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2404-2412, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2404-2412.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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