Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Flore Mietton, Elena Ferri, Morgane Champleboux, Ninon Zala, Danièle Maubon, Yingsheng Zhou, Mike Harbut, Didier Spittler, Cécile Garnaud, Marie Courçon, Murielle Chauvel, Christophe d’Enfert, Boris A. Kashemirov, Mitchell Hull, Muriel Cornet, Charles E. McKenna (), Jérôme Govin () and Carlo Petosa ()
Additional contact information
Flore Mietton: Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, Université de Grenoble Alpes, CEA, Inserm
Elena Ferri: Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus
Morgane Champleboux: Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, Université de Grenoble Alpes, CEA, Inserm
Ninon Zala: Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, Université de Grenoble Alpes, CEA, Inserm
Danièle Maubon: Laboratoire de Parasitologie-Mycologie, Institut de Biologie et Pathologie, CHU Grenoble Alpes
Yingsheng Zhou: Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus
Mike Harbut: California Institute for Biomedical Research
Didier Spittler: Institut de Biologie Structurale (IBS), Université de Grenoble Alpes, CEA, CNRS
Cécile Garnaud: Laboratoire de Parasitologie-Mycologie, Institut de Biologie et Pathologie, CHU Grenoble Alpes
Marie Courçon: Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, Université de Grenoble Alpes, CEA, Inserm
Murielle Chauvel: Unité Biologie et Pathogénicité Fongiques, Institut Pasteur, INRA
Christophe d’Enfert: Unité Biologie et Pathogénicité Fongiques, Institut Pasteur, INRA
Boris A. Kashemirov: Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus
Mitchell Hull: California Institute for Biomedical Research
Muriel Cornet: Laboratoire de Parasitologie-Mycologie, Institut de Biologie et Pathologie, CHU Grenoble Alpes
Charles E. McKenna: Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus
Jérôme Govin: Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, Université de Grenoble Alpes, CEA, Inserm
Carlo Petosa: Institut de Biologie Structurale (IBS), Université de Grenoble Alpes, CEA, CNRS

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15482

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