三株南海深海真菌抗结核活性代谢产物的研究

Mycobacteria (order Actinomycetales, family Mycobacteriaceae) are rod-shaped, Gram-positive, non-motile, obligate aerobic bacteria. The genus Mycobacterium have 85 species. Some Mycobacterium species, M. tuberculosis, M. bovis, M. microti, M. avium, M. leprae, and M. africanum, are higher animals intracellular pathogens. M. tuberculosis is a slow growing dormancy pathogen. Tuberculosis is an infective diseases spread by the air caused by the pathogen M. tuberculosis. The increased occurrence of multidrug resistant M. tuberculosis, the side effects of front -line antitubercular medicines, and the increased rate of tuberculosis related to HIV infections have led to recovered research interest in marine natural products in the discovery of new antitubercular drug leads. The risk of developing tuberculosis in HIV/AIDS patients is over one hundred times higher than in a normal person. Resistance to the antitubercular therapy is another serious issue. The ocean, with their unique biodiversity and chemodiversity, is a good candidate for new antitubercular drugs. Marine natural products have been reported to exhibit activity against M. tuberculosis and some have been chosen as leads for the development of new antitubercular agents. Growth in extreme environments deep fungi are important untapped source of production and use of novel biologically active substances, are untapped territory in antitubercular study. Searching for antitubercular from marine organisms is new trend to solve tuberculosis in recent years. Our prevoius study showed that three strains of South China Sea deep-sea sediments derived fungi crude extracts exsibited potential antitubercular activity, so we use this material for future study. This research is on multidiscipline cooperation of marine cell biology, marine microbiology,and marine natural products. Bioassay guide of antitubercular activity, isolation, and structure determination of antitubercular compounds by using chromatographic and spectral methods, and study structure–activity relationships for some of the more promising compounds, the use of proteomics technology initially revealed antitubercular mechanism of action of small molecule, laying the foundation for the development of a new deep-sea fungal origin antitubercular drugs.

结核病是由结核分枝杆菌引起慢性致死性疾病，是危害人类健康和导致人类死亡的重大传染性疾病，致死率仅次于艾滋病。由于不规范治疗、滥用抗结核药物等，结核菌耐多药菌株不断出现，给结核病的防治造成极大困难。研发新型高效低毒的抗结核药物对有效遏制结核病流行和提高结核病防治效果具有重要的意义。人类对新的抗结核药物需求越来越迫切，目前新抗结核资源的开发是研究热点。从深海真菌中寻找新的高效抗结核药物成为发现抗结核药物的新途径。本课题旨在通过天然产物化学，分子生物学和微生物学等多学科的配合，以结核菌为靶标，结合现代色谱学，波谱学，色谱-波谱联机技术，快速分离，鉴定三株南海深海真菌抗结核活性代谢产物，进行化学结构修饰，研究抗结核活性与结构关系，总结出活性药效团，并从活性代谢产物对结核菌细胞器的作用，以及对结核菌基因、蛋白表达，酶的作用等多角度探讨其初步作用机理，为研制南海深海真菌来源的新型抗结核药物奠定基础。

结核病是由结核分枝杆菌引起慢性致死性疾病，是危害人类健康和导致人类死亡的重大传染性疾病，致死率仅次于艾滋病。由于不规范治疗、滥用抗结核药物等，结核菌耐多药菌株不断出现，给结核病的防治造成极大困难。研发新型高效低毒的抗结核药物对有效遏制结核病流行和提高结核病防治效果具有重要的意义。人类对新的抗结核药物需求越来越迫切，目前新抗结核资源的开发是研究热点。从深海真菌中寻找新的高效抗结核药物成为发现抗结核药物的新途径。课题旨在通过天然产物化学，分子生物学和微生物学等多学科的配合，以结核菌为靶标，结合现代色谱学，波谱学，色谱-波谱联机技术，快速分离，鉴定三株南海深海真菌抗结核活性代谢产物，进行化学结构修饰，研究抗结核活性与结构关系，总结出活性药效团，并从活性代谢产物对结核菌细胞器的作用，以及对结核菌基因、蛋白表达，酶的作用等多角度探讨其初步作用机理，为研制南海深海真菌来源的新型抗结核药物奠定基础。 分离鉴定 208 个单体化合物，其中结构新颖的化合物51 个,发现 8 个抗结核活性强的化合物,发表 SCI 论文10篇；申请国内发明专利 2 项, 培养博士后 1 人，博士研究生 3 人，硕士研究生 2 人。