海洋真菌SCSIO GtR01梭链孢烷型抗感染先导物的定向挖掘及其内酯环形成机制研究

抗生素耐药性已严重威胁到人类健康，亟待寻找新的抗生素。梭链孢烷类抗生素具有靶向延伸因子EF-G的独特抗菌作用机制，还与其它临床常用抗生素无交叉耐药性，因而又重新受到关注。在前期研究中，我们从海洋真菌A. fumigatus SCSIO GtR01中分离得到一个梭链孢烷型化合物16-odeacetylhelvolic acid 21,16-lactone，并通过LC-DAD-MS检测发现其发酵液中尚有丰富的梭链孢烷型化合物。本项目拟采用HPLC-DAD-MS/MS和活性筛选相结合的方法，从菌株SCSIO GtR01中定向挖掘结构新颖、抗菌活性显著的梭链孢烷类先导化合物；此外，拟通过异源表达和体外酶学验证实验，阐明具有21,16-内酯环的梭链孢烷类化合物中内酯环形成的酶催化机制。本项目的实施，将会丰富梭链孢烷类抗生素的结构多样性，为研发具有自主知识产权的海洋抗菌药物奠定基础。

Antibiotic resistance has seriously threatened human health, and it is urgent to find new antibiotics. Owing to their unique antibacterial mechanism of targeting the elongation factor EF-G, and little cross-resistance with other clinically used antibiotics, fusidane-type antibiotics have drawn renewed attentions from the synthetic and pharmacological communities. In the previous study, a fusidane-type compound 16-odeacetylhelvolic acid 21,16-lactone was isolated from the marine fungus Aspergillus fumigatus SCSIO GtR01, and we found that there are still abundant analogues in the crude extract detected by LC-DAD-MS. This project is going to efficiently discover new bioactive fusidane-type compounds from fungus SCSIO GtR01 by HPLC-DAD-MS/MS combined with antibacterial activity screening. In addition, it is planned to apply heterologous expression and in vitro enzymatic verification experiments to clarify the enzymatic mechanism of 21,16-lactone ring formation in some fusidane-type compounds. The implementation of this project will enrich the structural diversity of fusidane-type antibiotics, and lay the foundation for the development of marine antibacterial drugs with intellectual property.