Antifungal targeting of an epigenetic pathway

Invasive fungal infections are a major global health threat, with over 6 million cases and 2.5 million deaths estimated annually worldwide. The rise of drug-resistant fungal strains and the limited number of antifungal drugs has created an urgent need for new therapeutic strategies.

We are exploring whether an epigenetic pathway involving histone acetylation can be targeted by small-molecule inhibitors as a novel antifungal approach.

Bromodomains (BDs) and BET proteins. Histone post-translational modifications (PTMs), such as lysine acetylation, regulate chromatin structure and function. Chromatin-binding proteins recognize these histone marks through modular domains called bromodomains (BDs), which recognize acetylated lysine via a hydrophobic binding pocket. BET proteins are transcriptional regulators that bind acetylated chromatin and contain two BDs. We discovered that a single BET BD can simultaneously recognize two acetylated lysines, revealing a new mode of combinatorial histone PTM readout [1]).

BET Inhibitors as potential antifungal agents. Recent years have seen an explosion of interest in BET BDs, with several small-molecule BET inhibitors being developed for cancer, diabetes, and cardiovascular and inflammatory disease [2]. In collaboration with French and U.S. partners, we explored whether selective inhibition of the fungal BET protein Bdf1 could be a viable antifungal strategy against Candida species, major fungal pathogens in humans.
We have shown that Bdf1 BD activity is essential for fungal viability and identified small molecules that inhibit either of Bdf1’s two BDs without affecting their human counterparts [3]. Medicinal chemistry optimization led to develop improved inhibitors and to a better understanding of inhibitor activity [4].

Breakthrough in antifungal BET Inhibitor development. A major challenge in developing antifungal BET inhibitors has been the need to inhibit both Bdf1 BDs simultaneously and the difficulty in assessing on-target antifungal efficacy. Recently, we identified an inhibitor that selectively targets both Bdf1 BDs over human BET BDs and established on-target antifungal activity by developing an innovative NanoBiT assay and "humanized" Candida strains, where Bdf1 BDs are replaced by human BDs. These efforts enabled us to identify a BET inhibitor that targets both Bdf1 BDs, inhibits a broad spectrum of Candida species, and shows efficacy in a pre-clinical infection model [5].

These findings establish a critical proof of concept and highlight the potential of BET inhibitors as a novel class of antifungal agents.

Read more about this research here.

Publications:
[1] Morinière J et al., Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 2009 461:664-8
[2] Ferri E et al., Bromodomains: structure, function and pharmacology of inhibition. Biochem Pharm 2016 106:1-18.
[3] Mietton F et al. Selective BET bromodomain inhibition as an antifungal therapeutic strategy. Nature Comm 2017, 8:15482
[4] Zhou Y et al., Towards More Potent Imidazopyridine Inhibitors of Candida albicans Bdf1: Modeling the Role of Structural Waters in Selective Ligand Binding. J Comput Chem 2022, 43:2121-2130
[5] Wei K et al., Humanized Candida and NanoBiT Assays Expedite Discovery of Bdf1 Bromodomain Inhibitors with Antifungal Potential. Adv Sci . 2025 Jan 16:e2404260