Humanized <i>Candida</i> and NanoBiT Assays Expedite Discovery of Bdf1 Bromodomain Inhibitors With Antifungal Potential
The fungal Bromodomain and Extra-Terminal (BET) protein Bdf1 is a potential antifungal target against invasive fungal infections. However, the need to selectively inhibit both Bdf1 bromodomains (BDs) over human orthologs and the lack of molecular tools to assess on-target antifungal efficacy hamper efforts to develop Bdf1 BD inhibitors as antifungal therapeutics. This study reports a phenyltriazine compound that inhibits both Bdf1 BDs from the human fungal pathogen Candida glabrata with selectivity over the orthologous BDs from the human BET protein Brd4. On-target antifungal activity is established by devising two yeast-based inhibition assays: a growth assay using humanized Candida strains in which the Bdf1 BDs are replaced by their Brd4 counterparts, and a NanoBiT assay that evaluates the BD-mediated association of Bdf1 with chromatin. These assays additionally enable the discovery that BET inhibitor I-BET726 targets both Bdf1 BDs, inhibits the growth of a broad spectrum of Candida species, including antifungal-resistant clinical isolates, and displays efficacy in an invertebrate animal model of infection. These collective findings highlight the promising potential of Bdf1 BD inhibitors as an innovative class of antifungal therapeutics and the pivotal role of yeast-based assay development toward achieving this end.
Authors
- Carlo Petosa (ORCID: https://orcid.org/0000-0002-9975-1167)
- Gaëlle Bourgine (ORCID: https://orcid.org/0000-0003-3584-4230)
- Muriel Cornet (ORCID: https://orcid.org/0000-0003-4155-3675)
- Charles E. McKenna (ORCID: https://orcid.org/0000-0002-3540-6663)
- Flore Mietton
- Marjolaine Noirclerc‐Savoye (ORCID: https://orcid.org/0000-0002-5481-6561)
- Kaiyao Wei
- Rose‐Laure Indorato
- Gwénaël Rabut (ORCID: https://orcid.org/0000-0003-2658-2769)
- B. A. Kashemirov (ORCID: https://orcid.org/0000-0001-7175-9960)
- Amédé Larabi
- Nathan J. Dupper
- Dimitrios A. Skoufias (ORCID: https://orcid.org/0000-0001-5595-3413)
- Jérôme Govin (ORCID: https://orcid.org/0000-0001-5511-6965)
- Timothy A. Dinh (ORCID: https://orcid.org/0000-0002-7601-1756)
- Justin M. Overhulse (ORCID: https://orcid.org/0000-0002-1902-9079)
- Morgane Champleboux (ORCID: https://orcid.org/0000-0003-0149-1289)
- Cécile Garnaud
- Marie Arlotto (ORCID: https://orcid.org/0000-0001-5079-5962)
- Yordan Hayat
- Jiayi Yang
- Yingsheng Zhou
- Hasan Dawi
Institutions
- Institut polytechnique de Grenoble (FR)
- University of Southern California (US)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Centre Hospitalier Universitaire de Grenoble (FR)
- CEA Grenoble (FR)
- Institut de génétique et de développement de Rennes (FR)
- Institut de Biologie Structurale (FR)
- Institut pour l'avancée des biosciences (FR)
- Université de Rennes (FR)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1002/advs.202404260
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- University of Southern California
- Fondation Innovations en Infectiologie
- Université Grenoble Alpes
- European Molecular Biology Laboratory
- Agence Nationale de la Recherche
- European Synchrotron Radiation Facility
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives
- Conseil National de la Recherche Scientifique
- French Infrastructure for Integrated Structural Biology
- National Institutes of Health