Discovery of Novel Fungal Lanosterol 14α-Demethylase (CYP51)/Histone Deacetylase Dual Inhibitors to Treat Azole-Resistant Candidiasis

Invasive
fungal infections (particularly candidiasis) are emerging
as severe infectious diseases worldwide. Because of serious antifungal
drug resistance, therapeutic efficacy of the current treatment for
candidiasis is limited and associated with high mortality. However,
it is highly challenging to develop novel strategies and effective
therapeutic agents to combat drug resistance. Herein, the first generation
of lanosterol 14α-demethylase (CYP51)-histone deacetylase (HDAC)
dual inhibitors was designed, which exhibited potent antifungal activity
against azole-resistant clinical isolates. In particular, compounds 12h and 15j were highly active both in
vitro and in vivo to treat azole-resistant
candidiasis. Antifungal mechanism studies revealed that they acted
by blocking ergosterol biosynthesis and HDAC catalytic activity in
fungus, suppressing the function of efflux pump, yeast-to-hypha morphological
transition, and biofilm formation. Therefore, CYP51-HDAC dual inhibitors
represent a promising strategy to develop novel antifungal agents
against azole-resistant candidiasis.