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Nat Commun. 2017 May 18;8:15482. doi: 10.1038/ncomms15482.

Selective BET bromodomain inhibition as an antifungal therapeutic strategy.

Author information

1
Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, Université de Grenoble Alpes, CEA, Inserm, 38000 Grenoble, France.
2
Institut de Biologie Structurale (IBS), Université de Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France.
3
Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus, Los Angeles, California 90089, USA.
4
Laboratoire de Parasitologie-Mycologie, Institut de Biologie et Pathologie, CHU Grenoble Alpes, 38043 Grenoble, France.
5
Laboratoire TIMC-IMAG-TheREx, UMR 5525 CNRS, Université Grenoble Alpes, 38058 Grenoble, France.
6
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, California 92037, USA.
7
Unité Biologie et Pathogénicité Fongiques, Institut Pasteur, INRA, 75015 Paris, France.

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.

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PMID:
28516956
PMCID:
PMC5454392
DOI:
10.1038/ncomms15482
[Indexed for MEDLINE]
Free PMC Article

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