黏细菌是重要的天然活性物质来源，发现的新骨架天然化合物超过100种，其中埃博霉素已经作为抗癌药物上市。基因组测序表明黏细菌中仍然有大量化合物有待发掘。但是黏细菌天然产物在本源菌中产量通常很低，生长缓慢，难于操作和遗传改造。因此将其生物合成基因转移到底盘菌中应用异源表达策略是黏细菌基因组挖掘的可行方法。前期研究发现埃博霉素能在异源宿主菌株DSM7029中稳定产生，该菌在生长培养和遗传操作等方面均优于黏细菌，具有成为表达黏细菌天然产物通用底盘菌的潜力。本项目拟建立并优化基于该菌自身噬菌体蛋白所介导的Red/ET同源重组系统，用于快速的基因组大片段删除和插入，实现基因组简化和改造，从而优化菌株的生长发酵属性、降低代谢背景；并利用转录组测序筛选高强度的启动子，通过提高转录水平增加目标化合物产量；最终使其成为人工表达天然产物系统的通用底盘菌，用于挖掘未知天然化合物和提高高价值化合物产量。

Myxobacteria are an important source of bioactive natural products, more than 100 novel scaffolds including the marketed anticancer drug lead epothilones. The genome sequencing also revealed there are still a huge number of compounds waiting for mining in myxobacteria. However, the yields of myxobacterial natural products are usual low in the native producers, and most of myxobacteria are slow-growing and genetically hard-to-manipulate strains. Thus transferring biosynthetic gene clusters into a simple chassis for heterologous expression is a feasible strategy of myxobacterial genome mining. Our preliminary study showed that epothilones were robustly produced in a heterologous host strain DSM7029, and its growth rate, cultivation and genetic manipulation are superior to myxobacteria. Thus this strain have the potential to be a general chassis. This project intends to construct and optimize the Red/ET recombineering system based on the native phage protein pairs for the rapid genome manipulation in DSM7029, to delete non-essential genes and insert some useful genes, thus to optimize the growth and fermentation characteristics and decrease the metabolite profile. Then to screen of several strong promoters by transcriptome sequencing for improving the yields of target compounds. In summary, this project is to use synthetic biology strategy to build a general chassis of artificial expression system of natural products for mining of unknown (myxobacterial) natural products and yield improvement of valuable natural products, such as epothilones.