Discovery of Novel Fungal Lanosterol 14α-Demethylase (CYP51)/Histone Deacetylase (HDAC) Dual Inhibitors to Treat Azole-resistant Candidiasis.
J Med Chem. 2020 Apr 29;:
Authors: Han G, Liu N, Li C, Tu J, Li Z, Sheng C
Invasive fungal infections (particularly candidiasis) are emerging as severe infectious diseases worldwide. Due to serious antifungal drug resistance, therapeutic efficacy of the current treatment for candidiasis are limited and associated with high mortality. However, it is highly challenging to develop novel strategies and effective therapeutic agents to combat with drug resistance. Herein, the first generation of lanosterol 14α-demethylase (CYP51)-histone deacetylase (HDAC) dual inhibitors were 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.
PMID: 32347094 [PubMed - as supplied by publisher]