Abstract
Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.
Highlights
Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies
In a study of the Mediator complex subunit Med[15], which interacts via its KIX domain with a transcription factor (Pdr1) implicated in pleiotropic drug resistance in C. glabrata, drug-resistant strains were re-sensitized to antifungals by a small-molecule inhibitor targeting the KIX domain–Pdr[1] interface[11]
Compound 3 showed relatively little cytotoxicity towards mammalian cells (EC50 4100 mM; Supplementary Fig. 6). These results demonstrate the feasibility of using a small-molecule inhibitor to antagonize CaBdf[1] function in the fungal cell
Summary
Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. In a study of the Mediator complex subunit Med[15], which interacts via its KIX domain with a transcription factor (Pdr1) implicated in pleiotropic drug resistance in C. glabrata, drug-resistant strains were re-sensitized to antifungals by a small-molecule inhibitor targeting the KIX domain–Pdr[1] interface[11] These findings point to an important role of chromatin-interacting proteins in fungal drug susceptibility. We demonstrate that Bdf[1] BD functionality is essential in C. albicans and identify small-molecule inhibitors that target Bdf[1] BDs without inhibiting human BET proteins, establishing Bdf[1] inhibition as a potential antifungal therapeutic strategy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
