塔克拉玛干沙漠药用微生物资源勘探与抗耐药菌新分子的发现

"ESKAPE" pathogens (Enterococcus faecium,Staphylococcus aureus, Klebsiella pneumoniae, Cinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species) occurred more and more serious in the world and antibiotic-resistant bacteria already became global challenge to public health. But new types of antibacterial drugs are so extremely limited that clinicians are forced to the situation as "Bad bugs, No drugs", which made new antibiotic discovery become very important and urgent issue. Pharmaceuitical microbiology, especially, actinomycetes were the main producing strain of antibiotics. After excavation for many decades, new antibiotics were more and more difficult to be found from the soil samples of common enviroment, since hundred of thousands of antibiotics were already studied. Those known antibiotics can't be used in clinic due to different reasons related to side-effect or physico-chemical properties etc and interfered the discovery of other new antibiotics unless new strategies, most directly, structural dereplication in the earlier discovering period to be used. On the contrary, the possibility to find new antibiotics from special enviroments such as Marine, Cave or Desert are increasing and became more and more hot and popular in the field of antibiotic discovery,especially in the developed countries, because microbes have to adapt and evolve in metabolite and gene level to resist the stress from their habitat,thus, have the capability to synthesize novel chemicals to carry out special biofunctions and bioactivities. In China, the trends in the field of antibiotic dicovery from special enviroments grew very slowly, because the sampling in special enviroments was very danger and difficult, the studies demanded researchers possess multidisciplinary knowledges and new strategies such as structural dereplication in the ealier period of the studies etc. Besides our recent progress in discovery of new antibiotics from Lop Nor region, a hyper-arid area in Xinjiang,the new growing trend of foreign researchers' exploration in Taklimakan Desert of Xingjiang impelled us to present the grant proposal to accelerate our bioprospecting of new species and new antibiotic from the largest desert and very famous aera known as the "sea of death" in China to break through the record of none of new antibiotic discovery from the hyper-arid enviroment and demonstrate the local microbes in the hyper-arid desert have great capacity to produce new types of antibiotics. This study will definitely make contribution to find new antibacterial drug for the public health and provide a excellent example to explore new antibiotics in desert enviromnet in China, thus cause emphasis on exploration of actinomycetes from natural resource in special ecosystem in China.

ESKAPE等为代表的耐药菌日益猖獗，对人类健康已构成严重威胁，世界范围内有效新型抗耐药菌分子又几近枯竭，凸显新型抗生素发现的重要性。放线菌等药用微生物是抗生素为主微生物药物的重要来源，经几十年反复挖掘和缺少已知抗生素早期微快准排重，从普通土壤来源放线菌中发现新抗生素越来越困难。栖息于特殊生态环境的微生物，面临逆境胁迫，为了生存，逐步进化出独特而发达的防御和代谢系统，具备合成功能独特，结构新颖，活性广泛的次级代谢产物潜力，从中发现新抗生素几率相对较高，已逐渐成为新的研究热点。在我国，由于采样危险、学科交叉、排重策略缺乏、关注不够等原因，进展缓慢。我们在地球旱极罗布泊发现新"菌"新"素"的研究结果加之国外同行在塔克拉玛干沙漠动向，促使我们尽快开展塔克拉玛干沙漠药用微生物发掘和抗耐药菌新抗生素发现，突破该沙漠新抗生素零记录，揭示极旱沙漠放线菌特殊性及产新抗生素优势，为我国创新微生物药物做出贡献

天然抗生素由微生物产生，地球生物学的最新研究成果及新抗生素发现困难的现状促进了从极端环境药用微生物资源中发现新抗生素的研究。沙漠中存在大量奇特的放线菌，发现新抗生素的潜力巨大。本研究在前期塔克拉玛干沙漠南麓药用微生物资源勘探和新抗生素发现的基础上，进一步开展了塔克拉玛干沙漠腹地放线菌资源的勘探及新抗生素发现工作，经过4年的研究，发现塔克拉玛干沙漠腹地存在大量放线菌，本研究获得664株放线菌，分布于50个菌属，其中链霉菌为优势菌属、微杆菌科菌株较多并且存在大量放线菌新物种和稀有菌株，本研究发表和鉴定共10个放线菌新物种，发现潜在新物种20个。通过抗菌活性筛选发现大量抗菌活性菌株，通过结合基因预测和化学结构预测的方法，发现及合成新抗生素10个，已知抗生素8个，其中由沙漠植物内生小单孢菌GP5S-7产生的玄奘霉素作为我国第一个沙漠放线菌来源的新抗生素，具有强抗革兰氏阳性菌活性，体外MIC值在0.1-0.5ug/ml，玄奘霉素分子量为1950，是目前分子量最大的，唯一一个含有4个糖单元的硫肽类抗生素。硫肽类抗生素由于水溶性差，无法静脉注射，由于吸收差，只能作为畜用类抗生素使用，目前已有2个已商品化。玄奘霉素4个糖单元将提高其水溶性，同时玄奘霉素产量高，20升发酵液能获得至少10毫克，这些优势为玄奘霉素成药性开发奠定了坚实的物质基础。除此之外，本研究在国际合作、新高通量筛选模型使用、排重方法的建立等方面均取得较好的研究成果，共获得专利2项，专利公开1项，实质审查1项，正在撰写的专利2项，发表论文SCI论文16篇、标注中文核心期刊11篇。培养硕士博士研究生15名。目前仍有很多研究成果在总结和撰写中。