Histone deacetylase Hos1 promotes the homeostasis of Candida albicans cell wall and membrane and its specific inhibitor has an antifungal activity in vivo.

Abstract

The rise of drug-resistant Candida albicans (C. albicans) has led to an urgent need for new therapeutic strategies. Histone deacetylases (HDACs) inhibition has been shown to limit fungal virulence while enhancing the efficacy of antifungal drugs against Candida. However, HDACs are highly conserved from yeast to humans, which has hindered the application of these inhibitors in the antifungal therapy. The aim of this study is to identify a suitable antifungal target and develop specific inhibitors targeting C. albicans HDACs. Based on sequence alignments, the HDAC Hos1 in C. albicans was proposed as a target for further investigation. We evaluated the impact of Hos1 on C. albicans pathogenicity using a murine model of disseminated candidiasis. Results showed that Hos1 null mutant caused less damage to mouse tissues. Additionally, we demonstrated that the reduced virulence was due to inhibition of cell wall O-mannan biosynthesis and altered metabolic flexibility, leading to decreased adaptability of C. albicans. Increased sensitivity of C. albicans to antifungal drugs was attributed to abnormal accumulation of ergosterol in the cell membrane. Furthermore, we identified Hos1 inhibitors from the ZINC database using molecular docking. These inhibitors exhibited highly specific inhibition of the deacetylation activity of C. albicans Hos1. Importantly, the inhibitors not only reduced colonization and invasion by C. albicans in vivo but also synergized with polyene drugs to combat C. albicans by causing abnormal accumulation of ergosterol. Our findings provide detailed insights into antifungal targets and a useful foundation for the discovery of antifungal drugs specifically targeting Candida.