病媒虫源中新颖结构的天然产物的发现与抗生素先导化合物的研究

The preliminary research indicates that the secondary metabolites from insect are important sources of the lead compounds by the insects natural products investigation at present, and it is also a new pathway to solve the bacteria resistant problem with the extensive use of the antibiotic and the emerging of the bacterial resistance continuous. Based on our related work earlier research on the fomite insect sources while human beings have been in lack of new structure antibiotics, this project have been screening a great deal of insect antimicrobial active components when their MIC value is less than 0.025 g/mL. These new constituents from secondary metabolites of the pathogenic media pests of mite, bug, and ants,through the active tracer separated antibacterial activity evaluation and analyse appling of chromatographic detection. Antibacterial activity compounds were purified and their structure were identified for developing the dozen kinds of insect nature products. We set up two segments of the extraction and separation tracer directional screening new technology, that have obtained successful a batch of new structure of the active natural compounds. The leading compounds of natural antibiotics 1-2 were find as new structure based on the determination of antibiotic effect. And above all, under guidance of the antibacterial action, new stucture of antibiotics compounds were find by structure optimization and the structure-activity relationship research . And this study promote the development of insects natural products in the field of nature organic chemistry . Furthmore, Our result of research is finally provide scientific data for creating new drugs in antibiotics exploring.

目前，昆虫天然产物方面的初步研究表明，虫源次生代谢物是新药先导化合物的重要来源，它是解决细菌多药耐药性问题的新途径。针对细菌耐药性的不断出现和缺乏新结构、新靶点的抗生素的问题，基于我们相关的前期研究工作，本项目拟从蝇、螨、蚁、臭虫等病媒害虫的次生代谢物中，通过活性示踪分离、抗菌活性评价和色谱检测分析，遴选出 MIC值小于0.025g/mL 的数十余种昆虫抗菌活性组分；采用高效液相制备色谱技术和综合多种色谱手段，分离纯化得到单体化合物; 鉴定化合物结构并验证抗菌活性。研究中建立生物相溶性两段提取法和示踪分离定向筛选新技术，并发现一批新结构的活性天然化合物。基于对这些化合物的抗生素效力测定结果，从中获取1-2个具有新结构的天然抗生素先导化合物；通过对先导化合物构效关系和抗菌机理研究,找到具有独特抗菌作用的新抗生素模板化合物；为发掘和创制抗生素新药提供科学依据，并促进昆虫天然产物化学研究领域拓展

目前，昆虫天然产物的初步研究表明，虫源次生代谢物是新药先导化合物的重要来源，是解决细菌多药耐药性问题的新途径。针对病原微生物及细菌耐药性的不断产生和缺乏新结构、新靶点抗生素的关键问题，本项目通过活性示踪、抗菌活性评价和色谱检测分析方法（HPLC-生物活性图谱），从病媒害虫的五谷虫(蝇)、九香虫（臭虫）、蝼蛄（杂食节肢）和独角仙（甲）等昆虫的提取物中，遴选出抗菌活性在MIC值小于0.015g/mL的昆虫次生代谢物组分；采用高效液相制备色谱技术和多种色谱综合手段，分离纯化并鉴定、表征和验证抗菌新化合物，寻找结构新颖、活性显著的新型抗生素的先导化合物。该研究成功建立了昆虫及节肢动物来源的天然产物示踪定向筛选新技术和生物相溶性两段提取法. 研究结果表明，在上述4种病媒害虫中，五谷虫提取物的抗菌活性最强且为广谱抗菌性，其它3种病媒害虫的提取物抗菌谱主要是抗革兰氏阳性菌（G+）如枯草芽孢杆菌(Bacillus subtilis)；完成了相关信息档案的构建。在该病媒害虫的活性次生代谢产物研究中，发现了8个抗菌活性化合物，包括2个首次被发现的新颖天然有机氟化物（2’-氟代苯甲酸乙氨基醇酯和2’-脱氧氟代腺苷），具有重要科学价值。该研究结果为解决抗病原微生物的耐药性提供了新的思路，并对今后昆虫源天然产物的研究有重要的借鉴作用。