Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15482
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Funding
- FRISBI [ANR-10-INSB-05-02]
- GRAL [ANR-10-LABX-49-01]
- FACE foundation (Partner University Fund)
- National Institutes of Health [1R21AI113704]
- Agence Nationale de Recherche [ANR-14-CE16-0027-01, ANR-11-PDOC-011-01, ANR-10-INBS-08, ANR-10-LABX-62-IBEID]
- EU FP7 Marie Curie Action [304003]
- USC Dornsife College of Letters, Arts and Sciences
- Chateaubriand Fellowship
- FINOVI fellowship from the Region Rhone Alpes, France
- Agence Nationale de la Recherche (ANR) [ANR-14-CE16-0027] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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