基于氨基酸导向培养策略的长枝木霉QD01代谢产物多样性及群体感应抑制活性研究

群体感应机制调控细菌的致病行为，是解决细菌耐药性问题的理想靶标。海洋真菌次级代谢产物结构多样且活性独特，是群体感应抑制活性化合物的潜在来源。前期从黄海海泥生境中获得一株具有群体感应抑制活性的真菌长枝木霉 QD01，初步研究发现其活性产物是环二肽类化合物。环二肽是群体感应系统中一类重要的化合物，既作为信号分子又作为抑制剂能够双向调节不同的群体感应系统。本项目拟以长枝木霉QD01为目标菌株，基于环肽生源途径采用氨基酸导向培养策略深入发掘该菌株次级代谢能力，以期获得更多结构种类的肽类化合物。继而采用多种群体感应模型进行体内外系统评价化合物的活性，探讨构效关系；同时利用计算模拟和蛋白质工程技术，解析活性化合物与群体感应受体蛋白的分子作用机理。本研究将为氨基酸导向培养策略在海洋真菌代谢产物的深入开发应用提供借鉴，为新型天然抗菌先导药物的研发提供科学依据。

Quorum sensing (QS) regulates virulence in many bacterial pathogens, and thus, it is an effective way to overcome antibiotic resistance by finding efficient QS inhibitors. Marine-derived fungi would probably produce diverse secondary metabolites which are regarded as the important source of leading compounds. Previous studies have shown that one cyclic dipeptide isolated from a marine-derived fungus Trichoderma longibrachiatum QD01, is the major compound possessing anti-QS activity. There is evidence that cyclic dipeptides are able to activate or antagonize quorum-sensing systems of bacteria, and they are considered to influence cell-cell signaling. Based on above research, the ability of secondary metabolism production of this fungus was further explored by amino acid-directed strategy to obtain more active components. The ability of anti-QS activity will be evaluated using QS system models in Chromobacterium violaceum and Pseudomonas aeruginosa. Then the interactions between active compounds and QS receptor protein will be studied. This study will providing a scientific basis for researching antibiotic lead compounds with novel structures and promoting the development of amino acid-directed strategy.