Nat. Commun. 8, 15482 (2017)

Credit: NATURE COMMUNICATIONS

Fungal infections are a major source of complications and morbidity in immunocompromised individuals, with limited treatment options available. Mietton et al. therefore sought to establish whether targeting Candida albicans Bdf1 (CaBdf1)—a member of the BET family of bromodomain (BD)-containing proteins that functions by binding acetylated histone tails—might have therapeutic potential. First the authors established that the two BDs within CaBdf1 are essential for viability in vitro and for virulence in a mouse model of infection. They then showed that CaBdf1 BDs were resistant to BET inhibitors effective against human BDs. The crystal structures of CaBdf1 BD1 and BD2 revealed features within their binding pockets divergent from those of human BDs, rationalizing the resistance to existing inhibitors and suggesting that selectivity toward CaBdf1 was achievable. The authors then screened a library of small molecules using a homogeneous time-resolved fluorescence assay to detect disruption of a BD's interaction with tetra-acetylated H4 peptides. The screen identified a dibenzothiazepinone scaffold with activity toward CaBdf1 BD1 and an imidazopyridine compound active toward CaBdf1 BD2, but not their human counterparts. These findings suggest that selective BET inhibitors are a potential new class of antifungal therapeutics.