嗜酸放线菌活性新骨架化合物的挖掘及其生物合成研究

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 streptomycetes could not satisfy current medical needs. Our previous study showed that, acidophilic actinomycetes derived natural products exhibited prominent structural novelty, rich biological activity, and significant medicinal potential. Guided by bioactivity results for anti-drug resistance microbes and anti-tumor models, by chemical screening results based on UHPLC-UV/Vis-HRMS/MS analyses, and by whole genome sequencing data, 5 isolates with distinguishing novel natural scaffold producing potent are selected. Then, a combination of microbiology, natural product chemistry, and molecular genetic strategies will be used to explore the secondary metabolic potential of selected strains. We intend to obtain a variety of natural medical leads with novel scaffolds or bioactivity using the chromatography, spectroscopy and reverse-docking methods. At last, the biosynthesis study will be carried out for selected bioactive new compound. Our ultimate purpose is to design a suitable strategy to cope with the bacterial drug-resistance problem and unfold a new way for the investigation of actinomycete derived new natural products.

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，对传统链霉菌资源的开发已无法满足现阶段医药诉求。我们前期研究发现，红壤嗜酸放线菌来源的天然产物结构新颖，生物学活性显著，创新药物开发潜力极为优秀。建立在耐药病原菌抑制活性筛选结果、基于UHPLC-UV-HRMS的化学分析以及全基因组测序数据的基础上，本项目锁定5株具有新骨架化合物产生潜力的高活性菌株作为出发菌株，充分运用微生物学、天然产物化学、分子遗传学等手段深挖菌株次级代谢潜力；在解析新产物结构的基础上运用多种生物学活性模型以及计算机反向分子对接的模拟筛选技术，充分发掘产物活性并获得一批高活性的全新天然先导化合物；最后对结构新颖、活性优异的1-2个产物进行生物合成及遗传调控研究，为产物开发铺平道路。最终为解决病原耐药性问题提供一条可能的解决方案，并开辟成熟、稳定的放线菌天然产物资源开发新途径。

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，对传统链霉菌资源的开发已无法满足现阶段医药诉求。我们前期研究发现，红壤嗜酸放线菌来源的天然产物结构新颖，生物学活性显著，创新药物开发潜力极为优秀。在前期研究的基础上，本项目锁定若干株具有新骨架化合物产生潜力的高活性菌株作为出发菌株，充分运用微生物学、天然产物化学、分子遗传学等手段深挖菌株次级代谢潜力；最终发现化合物64个，包括潜在的全新化合物59个（其中15个已成功解析结构）；鉴定3类天然产物生物合成基因簇；解析完成1类天然产物的生物合成途径；阐明1类天然产物的合成调控机制。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，中文核心期刊研究论文1篇。