Candida auris has become a fungal “superbug” and a significant global threat that has caused multiple outbreaks in hospitals around the world. Some strains of C. auris are resistant to all three major classes of antifungal drugs (azoles, polyenes and echinocandins), creating an urgent need for new antifungal therapeutic strategies. Bromodomains are epigenetic protein modules that recognize acetylated lysine residues such as those on the N-terminal tails of histones. Bromodomain and Extraterminal (BET) proteins are a family of bromodomain-containing proteins that regulate gene transcription, are integral for many cellular processes and have been investigated as drug targets to treat many human pathological conditions such as tumour development, inflammation and autoimmunity. BET proteins also exist in Candida species, and previous studies have shown that inactivating the bromodomains of the fungal BET protein Bdf1 compromises the viability of Candida albicans and Candida glabrata. This project explores BET bromodomains as potential antifungal drug targets in C. auris. It aims to show that BET bromodomain inhibition is a viable antifungal strategy, identify small molecules that selectively target fungal BET bromodomains, and elucidate their structure and mode of inhibition. I have determined the high-resolution crystal structures of the two bromodomains of C. auris Bdf1 and showed that their binding pockets are distinct from those of human BET bromodomains. I also studied 19 known BET inhibitors in homogeneous time-resolved fluorescence (HTRF) and yeast growth inhibition assays. These efforts identified compounds that inhibit Candida Bdf1 bromodomains with submicromolar IC50 values and exhibit antifungal activity in Candida growth assays. Furthermore, I revealed the binding modes of these compounds by solving their co-crystal structures with the targeted bromodomains and identified potential ways to increase their potency and selectivity towards fungal BET bromodomains. Overall, these findings highlight BET inhibition as a highly promising potential antifungal strategy against Candida auris.​
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