安莎是一类生物活性显著的大环内酰胺，该家族仅有200余个成员，但是产生了3个著名的药物先导，即抗结核利福霉素、抗肿瘤格尔德霉素和美登木素。然而，其溶解性差和肝毒性强等成药性不足，限制了该家族的新药研发。合成生物学对于复杂天然产物的结构优化，与化学合成相比有诸多优势；而且，安莎生物合成机制的丰富多样性，为其合成生物学结构优化，提供了极为理想的条件。是故，本申请项目拟从三个方面开展安莎的结构优化：1. 改造安莎生物合成调控基因，拓展安莎的结构多样性；2. 改造安莎生物合成结构基因，实现苯安莎和萘安莎的相互转化；3. 利用安莎生物合成后修饰反应，如氨甲酰化和环氧化，改善安莎的成药性；并开展安莎新衍生物的抗细菌、抗肿瘤活性与肝脏毒性评价，为安莎类化合物的新药创制奠定基础，对拓展天然药物化学的新研究领域有借鉴意义。

Ansamycins are a family of potent macrolactams in that three wellknown drug leads were discovered from two hundreds of compounds. However, the drug development progress of this class of natural products was hampered by the drawbacks of their druggability such as low solubility and evident hepatotoxicity. Synthetic biology has many advantages over synthetic chemistry in optimizing the structures of complicated natural products. Moreover, ansamycins have complex mechanism of biosynthesis, which affords desired status for structural optimizations by synthetic biology. Thus, in this project, we aim to improve the druggability of ansamycins through structural optimizations by three different approaches: 1. manipulating the putative regulator genes to expand the structure diversity of ansamycins, 2. modifying biosynthetic genes to link up the interconversion of benzenic and naphthenic ansamycins, and 3. modifying the structures of ansamycins by the carbamoyltransferases and/or epoxidases. All three approaches will afford new ansamycins that will be screened for their antibacterial and antitumor activity, and evaluated for their hepatotoxicity. This project is significant in exploring new fields of medicinal chemistry of natural products, and new approaches to drug discovery and innovation.