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Antimicrobial Agents and Chemotherapy, April 2003, p. 1220-1227, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1220-1227.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Genome-Wide Expression Profile Analysis Reveals Coordinately Regulated Genes Associated with Stepwise Acquisition of Azole Resistance in Candida albicans Clinical Isolates

P. David Rogers1,2,3* and Katherine S. Barker1

Departments of Pharmacy,1 Pharmaceutical Sciences, College of Pharmacy,2 Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 381633

Received 7 November 2002/ Returned for modification 13 November 2002/ Accepted 23 December 2002

Candida albicans is an opportunistic human fungal pathogen and a causative agent of oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients with AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC; however, with increased use of these agents treatment failures have occurred. Such failures have been associated with the emergence of azole-resistant strains of C. albicans. In the present study we examined changes in the genome-wide gene expression profile of a series of C. albicans clinical isolates representing the stepwise acquisition of azole resistance. In addition to genes previously associated with azole resistance, we identified many genes whose differential expression was for the first time associated with this phenotype. Furthermore, the expression of these genes was correlated with that of the known resistance genes CDR1, CDR2, and CaMDR1. Genes coordinately regulated with the up-regulation of CDR1 and CDR2 included the up-regulation of GPX1 and RTA3 and the down-regulation of EBP1. Genes coordinately regulated with the up-regulation of CaMDR1 included the up-regulation of IFD1, IFD4, IFD5, IFD7, GRP2, DPP1, CRD2, and INO1 and the down-regulation of FET34, OPI3, and IPF1222. Several of these appeared to be coordinately regulated with both the CDR genes and CaMDR1. Many of these genes are involved in the oxidative stress response, suggesting that reduced susceptibility to oxidative damage may contribute to azole resistance. Further evaluation of the role these genes and their respective gene products play in azole antifungal resistance is warranted.

* Corresponding author. Mailing address: Department of Pharmacy, University of Tennessee Health Sciences Center, Suite 513, Feurt Building, 26 South Dunlap St., Memphis, TN 38163. Phone: (901) 448-3719. Fax: (901) 448-1741. E-mail: drogers{at}utmem.edu.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1220-1227, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1220-1227.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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