Mediator regulation of transporters in fluconazole resistant C. albicans mutants

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DESCRIPTION (provided by applicant): C. albicans is the most prevalent human fungal pathogen and is a leading cause of hospital-acquired bloodstream infections. There is an approximately 40% mortality rate, and over 10,000 deaths per year in the U.S. associated with systemic candidiasis. Azole drugs have met with some success in controlling these infections. However, a recently released Center for Disease Control report 'Antibiotic resistance threats in the United States, 2013' prioritized azole resistant C. albicans as a 'serious' threat to human health in the U.S. In addition, azole resistance runs especially high in HIV/AIDS patients suffering from oropharyngeal candidiasis in the developing world that lack access to highly active antiretroviral therapy, resulting in high morbidity and mortality. Understanding the molecular basis of azole (and other anti-fungals) resistance is critical to reducing disease burden. Clinical isolates of azole resistant C. albicans, and other fungal pathogens, frequently contain gain of function mutations in zinc cluster transcription factors that result in increased transcription of multi-drug efflux pumps. Little, however, is known about the mechanism used by these hyperactive transcription factors to activate their targets. Mediator is a highly conserved co-activator complex that is necessary for transcriptional regulation of most eukaryotic genes. Individual subunits within Mediator can be divergent and regulate specific subsets of genes within particular organisms. We hypothesize that gain of function mutations in zinc cluster transcription factors confer specific interactions with certain subunits of Mediator, which promote transcriptional activation of multi-drug efflux pump genes and anti-fungal resistance. The objective of this exploratory proposal is to specifically determine how Mediator facilitates fluconazole resistance conferred by gain of function mutations in Tac1, a C. albicans zinc cluster transcription factor that regulates the transporters Cdr1 and Cdr2. Moreover, we will compare the mechanisms used by different Tac1 gain of function mutants in order to determine whether there is a common interaction that could be therapeutically targeted. Preliminary evidence suggests this mechanism could be dependent on Mediator subunits specific to fungi, further supporting the feasibility of such a therapeutic approach.