基于DESI-IMS技术的深海真菌抗耐药白色念珠菌活性成分靶向挖掘及其作用机制研究

The Drug-resistance of Candida albicans has bcome a severe clinical problem for curing candidiasis and no targeted drug therapy is currently available. Therefore, it is urgent to develop new therapeutic agents for drug-resistant C. albicans. Deep-sea derived fungi, growing in the extreme environments, exhibit various of specialties such as widespread distribution, richness of diversity and complex metabolic pathways. They have become important resources for marine drug researches and developments because of their novel and bioactive metabolites. In this project, we will focus on potentially active strains screened out from deep-sea derived fungi which can inhibit drug-resistant C. albican. Their distribution differences in metabonomics between confrontation and Individual culturing will be analyzed for targeted mining chemically defensive metabolites based on DESI-IMS technology. Inspired by OSMAC strategy, the targeted strains will be further cultured on a large-scale in PDB and solid culture in PDB and solid culture while the isolation, structure identification and the antifungal activities elucidation of the bioactive compounds will be carried out comprehensively. Moreover, the structure-activity relationship and the antifungal mechanisms of active compounds against drug-resistant C. albicans will be investigated. The project will provide a theoretical basis and technical supportal for the discovery of new lead compounds against drug-resistant C albicans.and lay a foundation for systematic research of medicinal resources from deep-sea derived fungi.

耐药白色念珠菌感染已成为念珠菌病治疗的临床难题，目前尚无针对性药物治疗，因此亟需研发新型抗耐药白念珠菌临床治疗药物。深海真菌生长于极端环境，具有分布广泛、多样性丰富、代谢途径复杂等特点，同时其次级代谢产物新颖性高、生物活性显著，已成为海洋药物研发的重要资源。本项目通过活性导向筛选深海来源具有抗耐药白色念珠菌潜力菌株，采用对峙生长法构建“真菌-白色念珠菌”化学防御体系，进一步基于新型的解吸电喷雾电离质谱成像（DESI-IMS）技术对其代谢组分布差异进行分析，锁定目标菌株代谢组中抗白色念珠菌化学防御成分；基于OSMAC策略，利用液体及固体两种培养基规模发酵，靶向分离鉴定抗耐药白色念珠菌活性次级代谢产物及其类似物；同时对活性显著的化合物进行构效关系及作用机制研究。本项目的开展将为新型抗耐药白色念珠菌先导化合物的发现提供理论基础和技术支持，同时也为深海真菌药用资源系统性研究奠定基础。

耐药白色念珠菌感染已成为念珠菌病治疗的临床难题，目前尚无针对性药物治疗，因此亟需研发新型抗耐药白念珠菌临床治疗药物。深海真菌生长于极端环境，具有分布广泛、多样性丰富、代谢途径复杂等特点，同时其次级代谢产物新颖性高、生物活性显著，已成为海洋药物研发的重要资源。本项目通过活性导向筛选深海来源具有抗耐药白色念珠菌潜力菌株，采用对峙生长法构建“真菌-白色念珠菌”化学防御系统，进一步基于新型的解吸电喷雾电离质谱成像（DESI-IMS）技术对其代谢组分布差异进行分析，锁定目标菌株代谢组中化学防御成分；基于OSMAC策略，利用液体及固体两种培养基规模发酵，靶向分离鉴定所筛选的深海真菌中抗耐药白色念珠菌活性次级代谢产物及其类似物；总共发现50个单体化合物，其中新化合物15个；此外，筛选获得10个具有抗白色念珠菌活性的化合物，7个MptpB抑制活性的化合物；同时也对活性显著的化合物进行了初步的构效关系及活性作用机制展开研究，初步确定其作用机理；本项目的开展将为新型抗白色念珠菌先导化合物的发现提供理论基础和技术支持，同时也为深海真菌药用资源系统性研究奠定基础。