2-烯烃基四氢吡喃类抗菌剂的异源生产及构效关系研究

2‑alkenyl-tetrahydropyran is a group of promising anti-fungal natural products. The aim of this subject is to: (1) characterize the biosynthetic gene cluster of 2‑alkenyl-tetrahydropyran in Trichoderma species; (2) heterologous production of 2‑alkenyl-tetrahydropyran followed by HPLC-DAD-guided isolation; (3) analyze the structure-activity relationships of the anti-fungal 2‑alkenyl-tetrahydropyran scaffold. Through these works, the genes that are responsible for the biosynthesis of 2‑alkenyl-tetrahydropyran will be clarified, and a series of novel 2‑alkenyl-tetrahydropyran analogues will be obtained. This will supply the references for the biosynthetic basis of this kind of compounds, and supply the new leading compounds for the natural anti-fungal agents. At the same time, this project will set a good example for using biosynthetic genes as tools to explore the structural diversity for the activity screening and SAR research of natural products.

2-烯烃基四氢吡喃类化合物为一类天然抗菌剂，对多株致病菌的抗菌活性与酮康唑相当；但该类结构在自然界分布较窄，发现较为随机，严重阻碍了该类抗菌剂的药物开发研究。本课题拟基于合成生物学理念，展开对2-烯烃基四氢吡喃类抗菌剂的生物合成基因簇挖掘、异源生产、HPLC-DAD导向分离、抗菌活性评价及计算机辅助的构效关系研究。研究内容包括：（1）探究2-烯烃基四氢吡喃类抗菌剂的生物合成机制；（2）通过异源表达其合成基因簇并辅以化学导向分离获得系列2-烯烃基四氢吡喃类结构；（3）通过系统抗菌活性评价阐明该类抗菌剂的构效关系。该研究成果不仅能为同类或类似结构的生物合成途径的解析及工程菌的构建提供理论依据及技术参考，也能为新类型抗生素类药物的开发提供物质基础。

2-烯烃基四氢吡喃类化合物是一类天然抗菌剂，对致病菌的抗菌活性与酮康唑相当；但该类结构在自然界分布较窄，发现较为随机，严重阻碍了该类抗菌剂的药物开发研究。本课题基于合成生物学理念，研究了木霉中2-烯烃基四氢吡喃类结构化合物生物合成基因簇，并成功在构巢曲霉中进行了异源表达，获得了系列新结构化合物。本研究为类似结构的生物合成途径的解析及工程菌的构建提供理论依据及技术参考，也为新类型抗生素类药物的开发提供物质基础，对提高PKS类型的真菌次级代谢结构多样性开发具有重要意义。