Azoles and Candida in AIDS-Transcriptional Regulation

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DESCRIPTION (provided by applicant): Candida albicans, a pathogenic yeast, is the cause of fungal infections in immune-compromised patient populations including AIDS patients. These infections are treated with antifungal drugs including the azole fluconazole. Extensive azole use has resulted in resistance which is a growing and significant problem. As molecular mechanisms of resistance are identified, it becomes important to understand the pathways which regulate these mechanisms in both susceptible and resistant strains. Currently, little is known about the transcriptional regulation of the ERG11 gene in C. albicans, the product of which is the target of the azole drugs and a biosynthetic step in the synthesis of ergosterol, the fungal equivalent of cholesterol. The Overall Goal of this research is to understand the interactions between azoles and C. albicans by studying the expression and regulation of genes associated with resistance. This proposal focuses on the transcriptional regulation of ERG11. The Specific Aims are: 1) To characterize regions of the ERG11 promoter that are important for transcriptional regulation. 2) To identify and characterize the transcription factors that regulate the ERG11 promoter. 3) To characterize the newly described ECM22 transcription factor in C. albicans for its effect on ERG11 and azole susceptibility; disruption of gene results in azole hyper-susceptibility. 4) To characterize additional C. albicans genes, identified by genomic approaches, that regulate azole susceptibility. The interactions between azoles and fungal cells, and the resulting azole drug resistance, will continue to be a clinically significant issue for the foreseeable future. Understanding the transcriptional regulation of ERG11 and of ergosterol biosynthesis, and understanding how fungal cells respond to azole drugs may lead to improvements in diagnosis, treatment and prevention of fungal infections and of resistance.