模拟自然环境的海洋细菌培养及新抗菌素的发现

There is an urgent need for novel antibiotics to fight against the infections caused by the increasingly drug-resistant microbial pathogens that still severely harm human health and life. The marine microbial secondary metabolites with structural and bioactive uniqueness and diversity are rich sources of the lead compounds for novel antibiotic discovery. The currently cultivable marine microorganisms for the discovery of new antibiotics are extremely limited. New cultural approaches to access the yet unexplored uncultivable microorganisms in the ocean are key for discovering novel bioactive compounds. This project has two specific aims. Aim I: To establish a new approach that enables the isolation and culture of previously uncultivable bacteria from marine sediments including those from the hydrothermal areas and cold seeps. In this approach, an ingenious technology Chamber Trap and an Environment Specific Incubator are applied to simultaneously simulate the native nutrition (high salt and low nutrition) and special environment (high pressure, low and high temperature, lack of oxygen, lack of sunlight) of the growth of marine bacteria. Aim II: To discovery novel antibiotics from the bioactive compounds-contained bacteria obtained from Aim I. This study has the possibility to discover over thirty novel antibiotics, including at least one lead compound for potential drug discovery. The data from this project will also provide a foundation for further investigation of marine microorganisms and their active substances.

不断出现的耐药菌感染性疾病依然严重危害人类健康和生命，需要抗耐药菌新药物。化学结构和生物活性新颖多样的海洋微生物的代谢产物是抗生素先导化合物或新药的重要来源。目前可培养的海洋微生物资源极为有限，研究提高海洋微生物可培养性的新方法并获取尚未涉足的新资源是新活性物质发现的关键之一。本项目在前期工作基础上深入，针对海洋微生物生长的特殊生态环境，用特制培养室和特境培养装置同时模拟其营养物质(包括高盐和低营养)和环境条件(高压、低温或高温、缺氧和缺阳光)，对海底(包括热液和冷泉区)沉积物的细菌进行培养分离和驯化培养，构建提高海洋微生物可培养性的新方法，获取细菌新资源并研究其抗菌活性物质。本研究可望发现30个以上的新活性物质，提供至少一个抗耐药菌先导化合物并初步阐明其构效关系和作用机制，为后续海洋抗生素侯选新药研发提供科学依据，并为海洋微生物及生物活性物质的进一步深入持续研究奠定基础。

不断出现的耐药菌感染性疾病依然严重危害人类健康和生命，需要抗耐药菌新药物。化学结构和生物活性新颖多样的海洋微生物的代谢产物是抗生素先导化合物或新药的重要来源。本项目运用建立的海洋微生物培养方法，从来自浙江舟山东海海域、广东汕尾南海海域和珠海淇澳岛红树林等地的100多种海洋样品中分离得到1000多株海洋微生物。通过活性筛选，获得了350多株具有抗菌或抗肿瘤活性的活性菌株。对其中的19种具有生物活性的海洋样品的化学成分进行了研究，发现了40多个新化合物，其中多数具有抗菌或抗肿瘤活性，包括2个具有较好抗耐药菌的先导化合物(弗霉素B和23-O-butyrylbafilomycin D)和3个抗脑胶质瘤活性强的先导化合物(Bagremycin C、Streptodepsipeptide P11A、Tripolinolate A)。本项目的研究发现已在国际主流SCI学术刊物发表论文16篇和投稿论文3篇，申请了中国国家专利9项(已授权专利3项)。本项目先导化合物的发现为抗耐药菌感染和抗胶质瘤新药的研究和开发提供了科学依据；本项目的实施也为课题组进一步深入持续研究海洋微生物及其生物活性物质奠定了坚实的基础。