A novel arylnaphthalene lignan analogue targets CYP51 to inhibit Cryptococcus neoformans growth.

JR20, a novel arylnaphthalene lignan derivative, exhibits potent antifungal activity against Cryptococcus neoformans (IC50 = 2.82 μg/mL) through dual mechanisms targeting CYP51 and mitochondrial function. Mechanistic studies combining molecular docking, transcriptomics, and biochemical assays confirmed JR20's specific binding to CYP51, significantly reducing ergosterol biosynthesis and causing membrane disruption (evidenced by SEM/TEM showing cell wall collapse and plasmolysis). Flow cytometry revealed fungal necrosis induction, while mitochondrial dysfunction was demonstrated through membrane potential loss, ROS accumulation, and ATP synthesis impairment. In vivo studies using a murine deep infection model demonstrated JR20's therapeutic efficacy, showing both anti-infective and anti-inflammatory properties. As a lignan derivative, JR20 represents a promising antifungal candidate addressing drug resistance through its unique dual-action mechanism, highlighting the potential of natural product research for developing novel antifungals against resistant pathogens.