真菌感染威胁人类健康，新一代低毒、高效抗真菌药物发现迫在眉睫。Nystatin是微生物来源抗真菌天然药物典型代表，由多烯大环内酯苷元骨架与GDP-海藻糖胺（GDP-脱氧糖胺糖基）耦合而成，活性特异、不易产生耐药，特别用于治疗深部真菌感染；而该药物水溶性较低、肾毒性较大等不足，限制其广泛应用。本研究基于构效关系分析，靶向Nystatin结构中的GDP-海藻糖胺，结合结构生物学、计算化学手段，阐述负责GDP活化糖基耦合的糖基转移酶（NsyDⅠ）的新颖作用机制，构建“NDP-糖基元件质粒/实体库”，辅以底物宽泛糖基转移酶的应用及理性设计手段，实现Nystatin糖基异构化的生物合成。本研究针对抗真菌药用天然产物；融合结构生物学/计算化学的催化机制阐述；及基于理性设计的生物合成等热点前沿科学问题，进行分子创新，结合药效学及ADME/T评价，发现药物先导物，丰富本领域相关研究的策略参考及理论依据。

Fungal infection poses a grave threat to human health and it is pressing to find new low-toxic, highly-effective antifungal drugs. Nystatin, formed by coupling between a polyene macrolide glycoside skeleton and GDP- trehalosamine, is a typical representative of natural antifungal drugs from microorganisms. Nystatin has specific activity and is not susceptible to drug resistance, and is particularly suitable for the treatment of deep fungal infection. However, its wide application is limited by its low water solubility and high renal toxicity. In our study, we aim to target GDP- trehalosamine in the Nystatin structure and elucidate the novel catalytic mechanism of GDP-activated glycosyl coupling by glycosyltransferase (NsyDⅠ) based on structure-activity relationship analysis, structural biology and computational chemistry. .The biosynthesis of Nystatin glycosyl isomerization will be achieved by constructing a NDP-glycosyl based plasmid/entity library, together with utilizing a glycosyltransferase with a wide-spectrum of substrates, and other rational design approaches. The catalytic mechanism of antifungal pharmaceutical natural products will be explored through an approach combining structural biology and computational chemistry. Moreover, novel drug leads will be discovered by integrating rational molecular entity innovation, pharmacodynamics, and ADME/T (absorption, distribution, metabolism, excretion, and toxicity) studies based on NsyDⅠ, and research strategies and theories in this field shall be enriched.