羊毛甾醇
脱甲基酶
唑
组蛋白脱乙酰基酶
化学
麦角甾醇
微生物学
药理学
抗药性
氟康唑
生物化学
生物
组蛋白
抗真菌
甾醇
基因
胆固醇
作者
Guiyan Han,Na Liu,Chenglan Li,Jie Tu,Zhuang Li,Chunquan Sheng
标识
DOI:10.1021/acs.jmedchem.0c00102
摘要
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.
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