在“后基因组时代”，基因序列导向的新天然产物发现模式genome mining有望引领又一个天然产物研究的热潮。多环特特拉姆酸大环内酰胺 (polycyclic tetramate macrolactam, PTM)是一类具tetramic acid结构单元及多环体系的大环内酰胺类化合物，具有新颖复杂的化学结构、显著的生理活性及独特的作用机制。生物信息学分析显示数据库中存在大量有待发掘的新PTM合成基因簇，本申请项目拟采用“基因簇组装─异源表达”的策略,开展新PTM类天然产物的发掘，同时开展新催化元件的功能研究，进一步通过组合生物合成拓展PTM类化合物的结构多样性，从而发现具有潜在开发价值的药物先导，为我国具有自主知识产权的新药创制奠定基础。本项目将生物信息学、微生物技术与天然产物化学有机结合，有望进一步拓宽新天然产物的发现模式，为其它类型天然产物的定向发掘研究提供借鉴。

In the postgenomic era, genome-guided natural product discovery (genome mining) is probably leading to another golden age of natural product research. Polycyclic tetramate macrolactams (PTMs) is a family of macrolactam natural products, which contain one tetramic acid and a polycyclic system with distinct structure, diverse biological activities and new mode of action. Bioinformatic analysis of genome sequences in database has revealed many novel PTM biosynthetic gene clusters. In this proposal, we are planning to identify new PTMs by “pathway assembly-heterologous expression” approach. Meanwhile, we will also investigate the function of new enzymes involved in the biosynthesis of PTMs. Then, we will try to create “unnatural” PTMs by combinatorial biosynthesis approach. This will further expand the structure diversities of the PTM family, which may provide new leads for future drug development. The organic integration of bioinformatics, microbial techniques and natural product chemistry in this project will be helpful to establish new method for the discovery of natural products, which will set the foundation for other related research.