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Long-term azole treatment of patients with chronicCandida albicans infections can lead to drug resistance. Gain-of-function (GOF) mutations in the transcription factor Mrr1 and the consequent transcriptional activation ofMDR1 , a drug efflux coding gene, is a common pathway by which this human fungal pathogen acquires fluconazole resistance. This work elucidates the previously unknown downstream transcription mechanisms utilized by hyperactive Mrr1. We identified the Swi/Snf chromatin remodeling complex as a key coactivator for Mrr1, which is required to maintain basal and induced open chromatin, and Mrr1 occupancy, at theMDR1 promoter. Deletion ofsnf2 , the catalytic subunit of Swi/Snf, largely abrogates the increases inMDR1 expression and fluconazole MIC observed inMRR1 GOF mutant strains. Mediator positively and negatively regulates key Mrr1 target promoters. Deletion of the Mediator tail modulemed3 subunit reduces, but does not eliminate, the increasedMDR1 expression and fluconazole MIC conferred byMRR1 GOF mutations. Eliminating the kinase activity of the Mediator Ssn3 subunit suppresses the decreasedMDR1 expression and fluconazole MIC of thesnf2 null mutation inMRR1 GOF strains. Ssn3 deletion also suppressesMDR1 promoter histone displacement defects insnf2 null mutants. The combination of this work with studies on other hyperactive zinc cluster transcription factors that confer azole resistance in fungal pathogens reveals a complex picture where the induction of drug efflux pump expression requires the coordination of multiple coactivators. The observed variations in transcription factor and target promoter dependence of this process may make the search for azole sensitivity-restoring small molecules more complicated.

Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance