Effects of the HDAC6/8 Inhibitor MC1568, Alone and in Combination With Fluconazole, in Non‐ Albicans Candida Species Infections

Fungal infections pose a severe health risk, particularly in immunocompromised individuals, with Candida species being a leading cause of bloodstream infections. The rise of non‐ albicans Candida (NAC) infections, accounting for 35%–65% of candidemia cases, underscores the urgent need for novel antifungal strategies. Current treatments, including echinocandins and azoles, are increasingly challenged by drug‐resistant strains. This study evaluated the antifungal efficacy of three clinically approved histone deacetylase inhibitors (HDACi)—Vorinostat, Romidepsin, and Tucidinostat—along with the HDAC6/8‐selective inhibitor MC1568, alone and in combination with Fluconazole. The Fluconazole/MC1568 combination exhibited significant synergistic effects, reducing biofilm formation and enhancing antifungal activity, particularly against C. guillermondii , C. lusitaniae , and C. tropicalis . In Galleria mellonella larvae, this combination increased survival by 70% in C. tropicalis infections. When tested in human retinal pigment epithelium (RPE) cells, three different MC1568/Fluconazole combinations displayed low toxicity. These findings highlight the potential of the HDAC6/8 inhibitor MC1568 as adjunct therapy to combat NAC infections, warranting further research to optimize antifungal efficacy while minimizing toxicity.