Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / PETOSA Carlo

Inhibiting 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 Bromodomains

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 [1]. 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. Our collaborators showed that BET BD functionality is essential for the viability of Candida albicans, an important human fungal pathogen. We developed a FRET-based assay to identify BET BD inhibitors and performed a high-throughput screen of 80,000 compounds. We identified a number of hits that selectively inhibited C. albicans 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 a dibenzothiazepine compound which exhibits antifungal activity against the appropriately sensitive C. albicans 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 promising antifungal therapeutic strategy [2].

Research goals

We aim to improve the potency and selectivity of our previously identified BET inhibitors against C. albicans to demonstrate translational potential into the clinic. We also aim to extend the search for antifungal targets to additional epigenetic proteins and other pathogenic fungi.

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