聚酮和聚肽天然产物对于微生物新药物的发现和发展至关重要，而耐药疾病的发展和新活性天然产物的严重短缺限制了微生物新药开发。青藏高原极端生境孕育着大量合成聚酮和聚肽的未知微生物资源，尤其是放线菌，从中发掘活性聚酮和聚肽将是解决这一瓶颈的重要途径。本项目拟以青藏高原不同极端生境的微生物为研究对象，首先通过聚酮和聚肽生物合成基因的分子系统发育分析，揭示聚酮和聚肽生物合成多样性及其生物地理分布；其次，对丰富度显著的生境土壤进行放线菌选择性分离、聚酮和聚肽生物合成的菌株筛选及生物活性研究，获得具有显著活性的聚酮和聚肽生产菌；再次，对代表性活性菌株进行次级代谢产物研究，发掘新结构和活性显著的聚酮和聚肽天然产物；最后，对新颖活性分子产生菌进行基因组测序，结合生物信息分析，发掘潜在的新生物合成簇。本项目的顺利实施，将会加快青藏高原极端生境微生物药物开发的进程，对于扩大药源具有重要意义。

Polyketides and polypeptides in natural products are critical to the discovery and development of new microbial drugs, however, the emergence of drug-resistant disease and the serious shortage of new bioactive natural products limit the development of new microbial drugs. A large number of unknown microbials, especially actinomycetes, producing polyketides and polypeptides, survive in the extreme habitats of the Qinghai-Tibet Plateau (QTP), from which mining polyketides and polypeptides will be a promising way to solve this bottleneck. In the project, the microbes of different extreme habitats in the QTP were investigated. Firstly, the biosynthesis diversity and biogeography of polyketides and polypeptides would be revealed by molecular phylogenetic analysis of their biosynthesis genes. Secondly, the significant bioactive actinomycetes producing polyketides and polypeptides would be obtained from the investigation of selective isolation of actinomycetes in special habitats showing high richness, positive screening of strains producing polyketides and polypeptides, as well as bioactivities study. Thirdly, the new and bioactive chemical entities pertaining to polyketides and polypeptides will be obtained through systematic isolation of secondary metabolites of representatively bioactive strains. Finally, the genome of new bioactive molecules producing strains will be sequenced, and underlying novel biosynthesis gene clusters will be mined based on bioinformatics analysis. The successful implementation of the project will accelerate the development of microbial drugs in extreme habitats of the QTP, which is of great significance for expanding the drug source.