基因组信息指导下两株高原放线菌中新型抗生素的发现研究

Bacterial resistance is a serious health problem in today’s clinical, and the emerging of multi-drug resistant bacteria has brought great obsession in clinical treatment，it’s urgent to develop the antibiotic with new structures and mechanism from the special microbial resources to respond the growing resistance status. Here, we will use the whole-genome sequencing of tibetan plateau soil derived arthrobacter actinomycetes as experimental material, and conduct the following active metabolite research based on the abundance of gene cluster, clear biological activity and particularity of resources. By the using of multiple fermentation strategies, efficient promoter and expression of heterologous gene to activate the potential biosynthesis gene cluster, and under the guidance of analysis antibacterial activity-gene-LC-UV-MS/MS combination of forecasting results, novel natural products will be obtained by targeted separation, thus it could deeply excavate the natural products with novel structures and anti-drug-resistant activity from the special resource actinomycetes. The researches can greatly increase the discovery of active natural products with novel structures, provide the foundation for the exploitation of new antibiotics, and bring important significance in the targeted active metabolite researches of other special habitat derived microorganism.

细菌耐药是现今面临的严峻医疗健康问题，多药耐药菌的层出不穷给临床治疗带来了极大的困扰，亟需从特殊的微生物资源中开发出新结构、新机制的抗生素来应对日益严重的耐药现状。本研究拟以全基因测序的青藏高原土壤来源节杆菌属放线菌为实验材料，将微生物资源的特殊性、生物活性的明确性及代谢基因簇的丰富性作为切入点进行活性次级代谢产物的挖掘研究。利用多手段发酵策略、高效启动子和异源表达的方式激活基因序列中的潜力生物合成代谢基因簇，在抗菌活性-基因-LC-UV-MS/MS相结合的分析预测结果指导下，对新颖活性天然产物进行靶向分离，从而深入地探索特殊生境来源放线菌天然产物结构新颖性和抗耐药菌活性。本研究的开展能够极大的提高新颖结构活性天然产物的发现几率，为新型抗生素的开发提供坚实的基础，并对其它特殊生境来源微生物活性代谢产物的针对性开发研究具有重要的意义。

青藏高原作为一个养分贫乏、降水少、辐射强、氧含量低的特殊生态系统，生境的特点造就了其独特的微生物资源优势。本项目针对四株已经明确基因信息的放线菌利用antiSMASH进行生物合成基因簇分析和潜在的次级代谢产物预测。重点对目标菌株（MG34）利用OSMAC、多效性策略等方式进行代谢潜能挖掘，从中获得四个具有抗菌活性的新颖脂肽类化合物。结合基因信息学分析，进一步阐明其生物合成途径。本项目能够为特殊生境来源微生物的次级代谢产物研究提供方法学上的可靠借鉴，也为我国创新药物开发研究提供坚实的实验基础。