Selective BET bromodomain inhibition as an antifungal therapeutic strategy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-05-18

AUTHORS

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, Carlo Petosa

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. More... »

PAGES

15482

References to SciGraph publications

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    8

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms15482

    DOI

    http://dx.doi.org/10.1038/ncomms15482

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1085434525

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28516956


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