癌症和感染性疾病严重威胁人类的公共卫生健康，这一状况随着临床耐药性的出现进一步恶化。包括抗生素在内的天然产物是药物发现和发展的主要源泉，但其数量和质量已无法满足当前对于活性小分子的筛选要求。由于结构的复杂性，采用化学合成的方法扩展结构的多样性往往面临巨大挑战。本项目以来源于微生物、作用机制新颖、兼具良好抗肿瘤和抗感染活性的天然产物类群——硫肽类抗生素作为研究对象，立足于生物合成的新策略，尝试利用微生物产生体系的优越性解决合成化学手段在创造复杂天然产物的结构多样性方面的不足。我们将选择多个不同类型的硫肽分子，通过代谢途径的比较研究揭示其生物合成机制的普适性和特异性。在此基础上，一方面在微生物体系中发展高效快速的结构衍生和大量制备的生物学方法，另一方面利用共性与个性相结合的遗传标记发掘自然界中的硫肽新成员，在丰富硫肽家族结构多样性的前提下开展抗肿瘤和抗感染活性的优化与相应的作用机制研究。

Cancer and infectious diseases pose serious threats to public health. This situation is becoming worse due to the progressively emerging drug resistance. Natural products, including antibiotics, remain a major source for drug discovery and development; however, the quality and quantity of available natural products have not kept pace with advanced technologies for high-throughput screening of active organic small molecules. Primarily because of the structural complexity, the diversification of natural products is often a tremendous challenge to the current approaches of chemical synthesis. In this project, we choose thiopeptide antibiotics (a class of microbial peptide natural products showing both the potent antitumor and anti-infective activities with new or uncovered modes of action) as the target molecules for development of a biosynthetic strategy and aim at the expansion of their diversity and utility by taking advantage of microbial producing systems. Comparative analysis of biosynthetic pathways of structurally different thiopeptide members will lead to the characterization of the generality and specificity in thiopeptide biosynthesis. On this basis, we will 1) develop highly effective, new biological approaches in recombinant microorganisms for structural diversity of thiopeptide antibiotics and their preparation in large scales by fermentation and 2) explore naturally occurring, new thiopeptide members according to the genetic features that encode the commonality and specificity of thiopeptide biosynthesis. The enrichment of diverse chemical entities will facilitate the optimization of biological activities for antitumor or anti-infection drug development and the investigation into associated modes of action upon the establishment of structure-bioactivity relationship.