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Antimicrobial Agents and Chemotherapy, April 2009, p. 1344-1352, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.00926-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Relative Contributions of the Candida albicans ABC Transporters Cdr1p and Cdr2p to Clinical Azole Resistance{triangledown} ,{dagger}

Sarah Tsao,1,2 Fariba Rahkhoodaee,1 and Martine Raymond1,2,3*

Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada H3T 1J4,1 Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6,2 Département de Biochimie, Université de Montréal, Montreal, Quebec, Canada H3C 3J73

Received 11 July 2008/ Returned for modification 25 August 2008/ Accepted 30 January 2009

Candida albicans frequently develops resistance to treatment with azole drugs due to the acquisition of gain-of-function mutations in the transcription factor Tac1p. Tac1p hyperactivation in azole-resistant isolates results in the constitutive overexpression of several genes, including CDR1 and CDR2, which encode two homologous transporters of the ATP-binding cassette family. Functional studies of Cdr1p and Cdr2p have been carried out so far by heterologous expression in the budding yeast Saccharomyces cerevisiae and by gene deletion or overexpression in azole-sensitive C. albicans strains in which CDR1 expression is low and CDR2 expression is undetectable. Thus, the direct demonstration that CDR1 and CDR2 overexpression causes azole resistance in clinical strains is still lacking, as is our knowledge of the relative contribution of each transporter to clinical azole resistance. In the present study, we used the SAT1 flipper system to delete the CDR1 and CDR2 genes from clinical isolate 5674. This strain is resistant to several azole derivatives due to a strong hyperactive mutation in Tac1p and expresses high levels of Cdr1p and Cdr2p. We found that deleting CDR1 had a major effect, reducing resistance to fluconazole (FLC), ketoconazole (KTC), and itraconazole (ITC) by 6-, 4-, and 8-fold, respectively. Deleting CDR2 had a much weaker effect, reducing FLC or KTC resistance by 1.5-fold, and had no effect on ITC resistance. These results demonstrate that Cdr1p is a major determinant of azole resistance in strain 5674 and potentially in other clinical strains overexpressing Cdr1p and Cdr2p, while Cdr2p plays a more minor role.

* Corresponding author. Mailing address: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montreal, Quebec, Canada H3C 3J7. Phone: (514) 343-6746. Fax: (514) 343-6843. E-mail: martine.raymond{at}umontreal.ca

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1344-1352, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.00926-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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