Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections.

Abstract

Invasive fungal infections remain a challenge due to lack of effective antifungal agents and serious drug resistance. Discovery of antifungal agents with novel antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual inhibitors with potent activity against resistant Candida albicans infections. To better understand the antifungal spectrum and synergistic mechanism, herein new CYP51/HDAC dual inhibitors were designed which showed potent invitro and invivo antifungal activity against C.neoformans and C.tropicalis infections. Antifungal mechanism studies revealed that the CYP51/HDAC dual inhibitors acted by inhibiting various virulence factors of C.tropicalis and C.neoformans and down-regulating resistance-associated genes. This study highlights the potential of CYP51/HDAC dual inhibitors as a promising strategy for the discovery of novel broad-spectrum antifungal agents.