第三讲用于筛选新药化合物的重要源泉.ppt

用于筛选新药‘化合物’的重要源泉 微生物来源的天然产物 主要内容 一、微生物是开发新药的重要源泉 二、稀有微生物（稀有放线菌）的 分离与培养 三、微生物来源样品的准备和样品库的设置 四、植物共生菌产物的研究与开发 五、海洋微生物产物的研究与开发 一、微生物是开发新药的重要源泉 I微生物的天然产物与新药 Novel bioactive compound-producing microorganisms, 1939-1996 Top-selling Pharmaceuticals 2000 Why Natural Products of Microbial Origin One /Third of Top-selling Pharmaceuticals are Natural Products or Its Derivative Wide Diversity in Therapeutic area(anti-infective, antitumor,hypolipaemic, immunosuppressant, antidiabetic,antiobesity etc.) and Chemical Structure (macrolide, B-lactam, antiracycline, terpenoid, sugers, peptide, nucleotide, etc.) Only limited no. of microbes are isolated Still large no. of microbes are waiting for isolation Reproducibility (Scale-up and large scale preparation) Pharmaceuticals of Microbial Origin 一、微生物是开发新药的重要源泉 生物活性分析（活性筛选） 传统筛选方法 致病微生物代表菌株（大肠杆菌、枯草杆菌、金黄色葡萄球菌、肺炎杆菌、白色念珠菌、曲霉等）和肿瘤细胞、动物模型。 理性筛选方法（定靶筛选方法） 体外酶系统、受体拮抗系统、特殊细胞、特殊微生物（耐药菌、营养缺陷型）等。 Solidifying agent for isolation medium Polysaccharide produced by ‘Pseudomonas elodea’ Wide use of plant tissue culture (stimulate the growth of plant) Selective isolation of rare actinomycetes Ultra-rare 1 Actinobispora 2 Actinomadura (rugatobispora) 3 Sporichthya 4 Planomonospora 5 Planobispora Rare 1 Streptosporangium 2 Micromonospora 3 Microbispora 4 Actinoplanes 5 Dactylosporangium 三、微生物来源样品的准备和样品库的设置 微生物的分离与纯化方法 弹土法 稀释法 显微镜 Isolation of actinomycetes as a source of natural products Selective isolation methods for actinomycetes Isolation medium solidified by agar or gellan gum Addition of calcium chloride Dry-heat treatment of soil samples Addition of antimicrobial agents Alkaline flooding solution containing skim milk(zoosporic actinomycetes) Alkaline isolation medium(zoosporic actinomycetes) Acidic isolation medium(eliminate of general bacteria) gellan gum * * Taxon Number of novel antibiotic- producing microorganisms Actinomycetes 4,528(70.1%) (Streptomyces Rare actinomycetes) (3,739 789) Fungi 1,243(19.2%) Bacteria