Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Nature Communications
Flore MiettonCarlo 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.

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Citations

Jun 21, 2017·Nature Chemical Biology·Stéphane Larochelle
Jun 18, 2019·European Journal of Immunology·Jorge Domínguez-AndrésMihai G Netea
Jul 6, 2019·Nature Reviews. Drug Discovery·Andrea G CochranRobert J Sims
Feb 26, 2019·International Journal of Microbiology·Kátia Santana CruzJoão Vicente Braga de Souza
Sep 23, 2018·The Journal of Antibiotics·Hao SuXueshi Huang
Jul 21, 2017·Assay and Drug Development Technologies·Anton SimeonovDoug Auld
Jan 10, 2021·Journal of Fungi·François DanionJean-Paul Latgé
Nov 25, 2020·Bioorganic & Medicinal Chemistry Letters·Qinghua Ren, Wenqian Gao
Jan 20, 2021·Signal Transduction and Targeted Therapy·Nian WangRui Kang
Mar 10, 2021·Bioorganic & Medicinal Chemistry Letters·Qinghua Ren, Wenqian Gao
Nov 14, 2019·European Journal of Chemistry·André Boltjes, Alexander Dömling
Aug 28, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Qianqian WangXiaojun Yao

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Methods Mentioned

BETA
acetylation
pull-down
isothermal titration calorimetry
histone acetylation
PCR
gel filtration
peptide array
FRET
X-ray

Software Mentioned

MolProbity
DiscoverX
Active
ray Detector Software ( XDS )
Coot
Phaser
Phenix
CCP4

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