安莎家族有多个著名药物先导，如抗结核利福霉素、抗肿瘤美登木素和格尔德霉素，其药用潜力值得发掘。安莎属于I型聚酮大环内酰胺，与I型聚酮大环内酯的结构类型丰富多样相比，自然界还可能存在多种安莎新骨架；此外，安莎的聚酮延伸单元和后修饰丰富多样，对其生物活性有显著影响。本申请项目拟开展安莎的新骨架发掘与合成和定向制造研究，包括：运用遗传学、天然药物化学和结构生物学等交叉的综合性研究手段，深度挖掘11酮新骨架安莎，获得有开发潜力的药物先导；针对结核分枝杆菌耐利福平的分子机制，通过改造延伸单元的类型和数目，合成新骨架“利福霉素”，以期发现抗耐药结核病新药；平行开展丙氨酰化酶的改造和基因挖掘研究，并系统地遗传改造橙色珍贵束丝放线菌ATCC31565Dasm19菌株，提高美登醇的产量，力图实现美登木素抗体偶联物的重要中间体—L-丙氨酰美登醇的高效合成，对探索天然药物发现与创新的新途径有重要意义。

The ansamycin family contains several well-known drug leads, such as anti-tuberculous rifamycins, antitumor maytansinoids and geldanamycins, indicating its high degree of druggability. Ansamycins belong to macrolactams that are synthesized by type I polyketide synthase (PKS). Compared with macrolides which are also synthesized by type I PKS, ansamycins are of lower diversity in structural types, indicating the potentiality of discovering more novel skeletons of this family. However, ansamycins have high diversity in extender units and post-PKS modifications, which has great influence on their bioactivities and provides opportunities for structure optimizations..In this project, we aim to novel skeleton panning, function-orientated biosynthesis and targeted-production of ansamycins. Specifically, through interdisciplinary and integrated approaches of genetics, medicinal chemistry of natural products and structural biology, we are going to obtain drug leads with R&D potential by thoroughly exploiting novel ansamycins of nonaketide. By targeting the mechanism of rifampicin resistance in Mycobacterium tuberculosis, we will carry out the design and biosynthesis of novel backbone rifamycin derivatives through engineering the types and numbers of extender units so as to find new anti-tuberculous drugs. We will try to attain high yield production of 3-O-L-alanyl maytansinol, the critical intermediate of antitumor antibody-maytansinoid conjugates by protein engineering and gene mining of alanylase in parallel, and systematically manipulating Actinosynnema pretiosum ATCC31565Dasm19 to increase the yield of maytansinol. This project is significant in exploring new approaches to drug discovery from natural products and drug innovation.