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Antimicrobial Agents and Chemotherapy, May 2005, p. 1745-1752, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1745-1752.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Candida albicans Zinc Cluster Protein Upc2p Confers Resistance to Antifungal Drugs and Is an Activator of Ergosterol Biosynthetic Genes

Sarah MacPherson,³ Bassel Akache,^1, Sandra Weber,⁴ Xavier De Deken,^4, Martine Raymond,⁴ and Bernard Turcotte^1,2,3*

Dept. of Medicine,¹ Biochemistry,² Microbiology and Immunology, Room H7.83, Royal Victoria Hospital, McGill University, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1,³ Institut de Recherches Cliniques de Montréal, 110 Pine Ave. West, Montréal, Québec, Canada H2W 1R7⁴

Received 23 November 2004/ Returned for modification 3 January 2005/ Accepted 24 January 2005

The human pathogen Candida albicans is responsible for a large proportion of infections in immunocompromised individuals, and the emergence of drug-resistant strains is of medical concern. Resistance to antifungal azole compounds is often due to an increase in drug efflux or an alteration of the pathway for synthesis of ergosterol, an important plasma membrane component in fungi. However, little is known about the transcription factors that mediate drug resistance. In Saccharomyces cerevisiae, two highly related transcriptional activators, Upc2p and Ecm22p, positively regulate the expression of genes involved in ergosterol synthesis (ERG genes). We have identified a homologue in C. albicans of the S. cerevisiae UPC2/ECM22 genes and named it UPC2. Deletion of this gene impaired growth under anaerobic conditions and rendered cells highly susceptible to the antifungal drugs ketoconazole and fluconazole. Conversely, overexpression of Upc2p increased resistance to ketoconazole, fluconazole, and fluphenazine. Azole-induced expression of the ERG genes was abolished in a upc2 strain, while basal levels of these mRNAs remained unchanged. Importantly, the purified DNA binding domain of Upc2p bound in vitro to putative sterol response elements in the ERG2 promoter, suggesting that Upc2p increases the expression of the ERG genes by directly binding to their promoters. These results provide an important link between changes in the ergosterol biosynthetic pathway and azole resistance in this opportunistic fungal species.

Present address: Pediatrics Department, Stanford University Medical Center, Stanford, CA 94305.

Present address: IRBHM, Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium.

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