源于海洋微生物的临床“超级病菌”新型抑制剂的发现

This project focus on one of the major global health problems, multidrug-resistant bacteria, on the basis of the research of metabolites of marine microorganisms and two marine fungi whose extracts showed antibiotic activities were obtained, we choose the main clinical superbugs as compounds screening model, and aim to find new clinical superbugs inhibitors from the marine microorganisms repository from the South China Sea. The techniques of combination will be employed for the de novo or enhanced production of structurally diverse active natural products, including biosynthetic pathways analysis, a strategy by regulating the related metabolic processes, and rerouting the carbon flux distribution in different ways, induction of substances or chemical signals existing in the ecosystems in which these microorganisms interact with other organisms in the culture processes, and through the interaction with clinical superbugs, the strains will be induced and stimulated. β-lactamase which is closely related to clinical problem of antibiotic resistance will be used as compounds screening model. A computer-assisted drug design method will be used for exploring the mechanism of active compounds, and will pave the way for the research and development of novel marine antibiotic drug leads from marine microorganisms.

本项目在原有的海洋微生物代谢产物的研究，而且已发现两株对耐药病菌有良好抑制效果的活性菌株的基础上，聚焦目前全球一个最紧迫的公共卫生问题—耐药性“超级病菌”的问题，选用我国主要的临床“超级病菌”为活性筛选模型，从南海海洋微生物资源库中寻找新的“超级病菌”抑制剂。采用制定的一套组合技术的方法以期获得高产和多样的新结构抗“超级病菌”活性物质，包括通过生源合成途径分析，调控其相关的代谢过程，改变碳架物质流在不同途径中的流量分布；在培养过程中引入菌株原生态环境中存在的关键物质或信号；通过临床“超级病菌”的胁迫作用，对活性菌株进行诱导、刺激。选择与临床多种耐药细菌抗药性密切相关的β-内酰胺酶为模型进行化合物的活性筛选，采用计算机辅助药物设计的方法初步探讨抗临床“超级病菌”活性物质的作用机理，为寻找海洋微生物来源的抗临床“超级病菌”的新型海洋药物先导物打下基础。

本项目以海洋微生物为研究对象，完成了对多株海洋微生物菌株的研究，包括菌株的发酵培养、次级代谢产物的分离、结构鉴定、活性测试工作，并选择本课题组菌种库中部分菌株再次进行抗菌活性筛选。在该项目的资助下，共分离获得了79个海洋微生物来源的化合物并确定了它们的结构，其中获得新结构化合物22个，并研究了新化合物的生物活性，获得了具有抗菌活性的化合物2个。以通讯作者发表SCI论文5篇，以第二作者发表SCI论文1篇，以其他作者发表SCI论文2篇。另外，通过对本课题组菌种库中部分菌株的筛选，共获得具有抗菌活性的菌株26株。以上成果为获得海洋微生物来源的海洋药物先导化合物打下了一定的基础。