Epigenetic targets in pathogenic fungi

Invasive fungal infections are a major global health concern, with 2 million cases and >800,000 deaths estimated annually worldwide. An increase in drug-resistant fungal strains and the limited repertoire of available drugs has led to an urgent need for novel therapeutic agents.

BET proteins are transcriptional regulators that recognize acetylated chromatin through their two bromodomains (BDs), which specifically bind acetylated lysines within histone tails. Small-molecule inhibition of human BET BDs has been validated as a therapeutic strategy against cancer, inflammatory disease, and other medical disorders. This led us to wonder whether BET inhibition might be a useful strategy against invasive fungal infection.

In collaboration with French and U.S. partners, we investigated the possibility of selectively inhibiting fungal BET BDs as an antifungal strategy against Candida species, important human fungal pathogens. Using high-throughput chemical screening we identified a number of hits that selectively inhibited Candida BDs compared to the human homologs and determined the BD-bound crystal structures of these compounds, revealing the structural basis of selective inhibition. Moreover, we identified certain compounds that exhibit antifungal activity against sensitive Candida strains. These findings identify BET BDs as antifungal drug targets that can be selectively inhibited without antagonizing human BET function, thereby establishing BET inhibition as a potential antifungal therapeutic strategy.

Crystal structure of a BET bromodomain from C. albicans bound to a selective small-molecule inhibitor.