Targeting fungal BET bromodomains as a pan-Candida antifungal strategy

Wei, K.; Overhulse, J. M.; Arlotto, M.; Zhou, Y.; Dupper, N. J.; Kashemirov, B. A.; Garnaud, C.; Bourgine, G.; Cornet, M.; Rabut, G.; McKenna, C. E.; Petosa, C.; Govin, J.

doi:10.1101/2023.02.03.527073

bioRxiv · 10.1101/2023.02.03.527073

Targeting fungal BET bromodomains as a pan-Candida antifungal strategy

Wei, K.·Overhulse, J. M.·Arlotto, M.·Zhou, Y.·Dupper, N. J.·Kashemirov, B. A.·Garnaud, C.·Bourgine, G.·Cornet, M.·Rabut, G.·McKenna, C. E.·Petosa, C.·Govin, J.

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Abstract

Small molecules that target one or both bromodomains (BDs) of human BET proteins are intensely studied as potential new therapeutics against cancer, diabetes and other diseases. The BDs of the fungal BET protein Bdf1 are essential for the human fungal pathogen Candida albicans, suggesting BET inhibition as a potential antifungal strategy. However, while the inactivation of both Bdf1 BDs is lethal, that of a single BD only modestly affects viability, implying the need to develop antifungal compounds that selectively target both Bdf1 BDs without inhibiting human BDs. Here, we investigate Bdf1 as a potential antifungal target in Candida glabrata, an invasive Candida species phylogenetically distant from C. albicans and of increasing medical concern. We show that Bdf1 BD functionality is essential in C. glabrata and identify a phenyltriazine derivative that targets both Bdf1 BDs with selectivity over human BET BDs. We show that human BET BDs can functionally replace Bdf1 BDs in C. glabrata and we use the humanized strains to demonstrate on-target antifungal activity of the phenyltriazine compound. Moreover, by exploiting the humanized and parental fungal strains we identified BET inhibitor I-BET726 to have potent antifungal activity against a broad spectrum of Candida species, including azole- and echinocandin-resistant clinical C. albicans and C. glabrata isolates. Crystal structures suggest how to improve the potency and selectivity of these compounds. Taken together, our findings provide compelling support for the development of BET inhibitors as potential pan-Candida antifungal therapeutics.

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Wei, K., Overhulse, J. M., Arlotto, M., Zhou, Y., Dupper, N. J., Kashemirov, B. A., Garnaud, C., Bourgine, G., Cornet, M., Rabut, G., McKenna, C. E., Petosa, C., Govin, J.. 2023-02-04. Targeting fungal BET bromodomains as a pan-Candida antifungal strategy. https://doi.org/10.1101/2023.02.03.527073

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