H+、Fe3+介导的红壤嗜酸放线菌活性、"隐性"抗生素资源研究

The frequent emergence of multi-drug resistant pathogenic microbes and the decreasing number of brand new drugs placed on the market has severely threatened mankind's health, however, traditional actinomycete resources could not meet current medical needs. As a group of novel microorganism resources isolated from acidic soil, acidophilic actinomycetes exhibit abundant taxonomic variety, rich biological activity and prominent secondary metabolic potential. The production of their natural antibiotics were closed related to the H+, Fe3+ in the environment, and many antibiotics were not recognized previously thus to be "silenced". Based on primary screening for anti-microbes and anti-tumor models, secondary screening for PKS and NRPS genes and final screening for chemical entities guided by the HPLC-UV/VIS-MS/MS analyses, several distingwishing isolates which fully reflected resource characters of acidophilic actinomycete antibiotics were selected. In this project, we intend to optimize their antibiotic producing parameters and utilize the chromatography, spectroscopy and reverse-docking methods to make comprehensive understanding of their resource potential and to obtain a variety of natural medical leads with novel scaffolds or bioactivity as chemical evidences for screening and identification of unknown secondary metabolite biosynthetic gene clusters of acidophilic actinomycetes, and as chemical bases for the ecological function investigation of acidophilic actinomycetes.

耐药病原的肆虐和新抗生素研发速度的滞后使人们的健康面临严峻考验，对传统放线菌资源的开发已无法满足现阶段医药需求。作为一类新资源，红壤嗜酸放线菌多样性丰富、生物活性好、次级代谢潜力突出。前期研究发现，其天然抗生素的产生往往与环境中的H+、Fe3+密切相关，并可产生多种在常规筛选模型下无明显生物学活性的天然产物-即"隐性"抗生素。经耐药菌及肿瘤抑制模型初筛，PKS、NRPS等基因复筛和基于HPLC-UV/VIS-MS/MS的产物筛查后，本项目优选出若干株代表菌株，充分开发其次级代谢潜力，并运用现代色谱、波谱学手段及计算机反向分子对接等新技术，深度发掘其天然抗生素资源并评估其成药潜力，最终获得一批新活性、新结构的天然先导化合物。一方面为嗜酸放线菌未知次级代谢产物合成基因簇的筛查与鉴定提供化学证据，另一方面为探索嗜酸放线菌的生态功能奠定化学基础。最终建立成熟、稳定的放线菌资源开发新途径。

耐药病原的肆虐和新抗生素研发速度的滞后使人们的健康面临严峻考验，对传统放线菌资源的开发已无法满足现阶段医药需求。作为一类新资源，红壤嗜酸放线菌多样性丰富、生物活性好、次级代谢潜力突出。本项目采用“菌株分类--次级代谢编码基因--生物活性--HPLC-MS--化合物预测”的手段，对本类资源的600株菌进行系统分类学梳理，对其中的107株菌进行了次级代谢产物初筛，进而发现了125个潜在的新化合物。进一步的，采用传统培养发酵及分子遗传学手段相结合的方法，并运用现代色谱、波谱学手段及计算机反向分子对接等新技术，发掘了一批天然新骨架化合物并评估了其成药潜力。到目前为止，在本基金的支持下项目组已累计发表SCI研究论文4篇。