Discovery of BRD4-HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans

Over the past several decades, invasive fungal infections, especially candidiasis, have caused dramatic morbidity and mortality due to ineffective antifungal drugs and severe drug resistance. Herein, new BRD4-histone deacetylase (HDAC) inhibitors were designed to restore the susceptibility of Candida albicans (C. albicans) to fluconazole (FLC). Interestingly, several compounds showed excellent selectivity against fungal HDACs. In particular, compound B2 showed excellent synergistic effect with FLC against resistant C. albicans (FICI = 0.063) with high selectivity against fungal HDACs (SI = 1653) and low cytotoxicity. Compound B2 effectively synergized with FLC and prevented biofilm formation and morphological transition in resistant C. albicans, potentiating the antifungal activity of FLC in vivo and significantly reducing kidney fungal loads. Thus, this drug combination is promising in the treatment of resistant C. albicans infections.

Automated summary

Invasive fungal infections, particularly candidiasis, have become a significant cause of morbidity and mortality due to lack of effective antifungal drugs and drug resistance. A new class of BRD4-histone deacetylase (HDAC) inhibitors has been designed to restore susceptibility of Candida albicans to fluconazole. One compound, B2, has shown excellent selectivity against fungal HDACs, synergistic effect with fluconazole, and low cytotoxicity. In vivo studies have demonstrated that B2, in combination with fluconazole, effectively reduces fungal loads and prevents biofilm formation and morphological changes in resistant C. albicans, suggesting its potential for treating resistant candidiasis.