源于冠突散囊菌和细菌共培养的新结构活性次生代谢产物的研究

Infections due to resistant bacteria result in longer course of therapy ,increased hospital stays and higher mortality rates than those due to susceptible pathogens. Cancer represents one of the most severe health problems worldwide. Given the antibiotic resistance and a limited number of cancer chemotherapies, the discovery of new antibacterial and anti-cancer chemotherapeutic agents is a key goal for natural product and medicinal chemists. Natural product and/or natural product structures from microbe continued to play significant role in the during discovery and development process. Many important medicines have been discovered or derived from microbial secondary metabolites, such as the penicillin as antibiotics, lovastatin as an anti-cholesteremic agent, cyclosporin A as an immuno-suppressive agent. This proposal aims at the discovery of new antibacterial and antitumor secondary metabolites with unique structural features from co-culture of fungi and bacteria on the basis of the inhabit and living strategy. In this proposal, the secondary metabolite library will be prepared from the co-cultures of Eurotium cristatum and bacteria, and faster chemical isolation, and, most importantly, rapid identification of antibacterial and antitumor compounds will be obtained by application of chemical means(LC-UV and LC-MS) and biological screen. The discovery of new bioactive metabolites not only might provide candidates for the discovery of antitumor leads with therapeutic potential, but also might expand the source for compounds with antibacterial and antitumor properties.

人类正面临细菌耐药性困扰，加之不合理滥用抗菌药物，从而造成更多感染和更大的死亡风险；恶性肿瘤是威胁人类健康的主要杀手，而目前市场上仍然缺乏高效的抗肿瘤药物，因此针对细菌耐药性和恶性肿瘤的创新药物研制变得日益迫切。微生物是药物发现领域中重要的活性天然产物来源，人类已经从中发现多种治疗重大疾病的药物。本项目拟以冠突散囊菌和细菌二元组合共培养，通过多培养基发酵建设代谢产物库，采用LC-UV和LC-MS联用技术以及抗细菌和抗肿瘤活性筛选，应用微量分离技术高效发现新结构活性化合物。本研究将有助于拓展抗细菌和抗肿瘤活性物质的来源，为发现具有自主知识产权、高效、新型的抗细菌和抗肿瘤药物先导化合物奠定基础。

微生物是药物发现领域中重要的活性天然产物来源，人类已经从中发现多种治疗重大疾病的药物。然而经过大规模筛选后，目前已经很难从普通微生物中发现新结构活性化合物，已知化合物的重复发现浪费了大量的时间、人力、物力和财力。因此人们开始探索应用微生物共培养形成竞争性生态压力和激活沉默基因簇等非传统方法以提高普通微生物次生代谢产物结构和活性的多样性。本项目以冠突散囊菌和细菌二元组合共培养，通过多培养基发酵建设代谢产物库，采用LC-UV和LC-MS联用技术以及抗细菌和抗肿瘤活性筛选，应用微量分离技术高效发现新结构活性化合物。通过课题实施，优化了冠突散囊菌与细菌共培养的发酵条件，建立了近60个共培养粗提物样品库，优选冠突散囊菌和金黄色葡萄球菌为共培养目标体系，从其发酵粗提物中分离获得并鉴定纯化合物35个，其中新化合物4个。通过对获得化合物的活性评价，发现具有肿瘤细胞毒活性化合物10个，抗细菌菌活性化合物5个，抗真菌活性化合物2个。本研究验证了应用微生物共培养方法来丰富代谢产物结构和活性多样性的可行性和合理性，有助于拓展抗细菌和抗肿瘤活性物质的来源。