Controlling antifungal activity with light:Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors  

作　　者：Zhuang Li Na Liu Wanzhen Yang Jie Tu Yahui Huang Wei Wang Chunquan Sheng 

机构地区：[1]State Key Laboratory of Bioengineering Reactor,And Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science&Technology,Shanghai 200237,China [2]School of Pharmacy,Second Military Medical University(Naval Medical University),Shanghai 200433,China [3]Department of Pharmacology and Toxicology,College of Pharmacy,And BIO5 Institute,University of Arizona,Tucson,AZ 85721,USA

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3080-3092,共13页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation(81725020,82003591 and 81973175,China);the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-07-E00073,China);Science and Technology Commission of Shanghai Municipality(20S11900400,China)。

摘　　要：Invasive fungal infections(IFIs)have been associated with high mortality,highlighting the urgent need for developing novel antifungal strategies.Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14a-demethylase(CYP51)inhibitors.The photocaged triazoles completely shielded the CYP51inhibition.The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4%and 83.7%,respectively.Importantly,the shielded antifungal activity(MIC80≥64μg/m L)could be efficiently recovered(MIC80=0.5—8μg/m L)by light irradiation.The new chemical tools enable optical control of fungal growth arrest,morphological conversion and biofilm formation.The ability for highprecision antifungal treatment was validated by in vivo models.The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model.Overall,this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

关 键 词：Antifungal agents Ergosterol biosynthesis TRIAZOLES Photocaged Optical control 

分 类 号：R91[医药卫生—药学]