New Ketolide Antibacterial Drugs

新型酮内酯类抗菌药

• 批准号: 6443213
• 负责人: CHARLES R HUTCHINSON
• 金额: $ 23.37万
• 依托单位: KOSAN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6443213
• 关键词: Escherichia coli; Streptomyces; antibacterial agents; bacteria infection mechanism; bacteriolysis; biotechnology; biotherapeutic agent; biotransformation; cholinesterases; coenzyme A; combinatorial chemistry; drug design /synthesis /production; drug discovery /isolation; drug resistance; enzyme activity; enzyme biosynthesis; erythromycin; macrolide antibiotics; microorganism disease chemotherapy; microorganism immunology; molecular genetics; polyketide synthase; polymerase chain reaction

LONG TERM GOAL: Production of novel ketolide antibiotics with potent antibacterial activity against macrolide susceptible and resistant bacterial pathogens. PHASE I: We will develop a biological process for production of 15-methyl-6- deoxyerythronolide B, the precursor of 15-methylerythromycin A, through genetic engineering of the 6-deoxyerythronolide B polyketide synthase. This will be accomplished by optimizing the biosynthetic pathway of a substrate used to make the target compound in Streptomyces coelicor, a related actinomycete strain of Escherichia coli. That substrate will be used by an engineered 6-deoxyerythronolide B polyketide synthase to make 15-methyl-6-deoxyerythronolide B, which will be isolated and bioconverted to 15-methylerythromycins by a strain of Saccharopolyspora erythraea or directly to this compound by an engineered strain of Streptomyces fradiae that contains the genes for production of 15-methyl-deoxyerythronolide B and the 15- methylerythromycins. PHASE II: This process will be optimized for large scale production of 15- methyerythromycins that will be used to make ketolide antibiotics in sufficient amount for preclinical and clinical development. Kosan has discovered a lead ketolide in partnership with The R.W. Johnson Pharmaceutical Research Institute and expects that this compound or a close analog will be developed into a drug that is competitive with the two current front runners in this area. PROPOSED COMMERCIAL APPLICATIONS: There is a growing need to discover and develop noel antibiotics that can overcome resistance mechanisms. The proposed research will generate modified macrolide antibiotics which are effective against macrolide resistant organisms. Since world-wide sales of macrolide antibiotics exceed $3B per year, these new antibiotics should have significant commercial value.

长期目标：针对大环内酯类药物易感和抗性细菌病原体具有有效的抗菌活性的新型酮化剂抗生素的产生。第一阶段：我们将通过通过6-脱氧胆碱化乙烯醇B聚酮化合物合酶的基因工程来开发生产15-甲基-6-脱氧乙基胆碱B的生物学过程。这将通过优化用于使靶化合物在链霉菌Coelicor（一种相关的大肠杆菌的放线菌菌株）中的底物的生物合成途径来实现。该底物将由工程设计的6-脱氧醚胆碱B聚酮化合物合成酶制造15-甲基-6-脱氧醚醇B，将其隔离并通过生物体转化为15-甲基thrymycins菌株，由囊孢子菌的菌株或直接用于固定的菌丝的菌株，或者直接通过固定的菌株来构成菌株，以使其具有固定性的菌株，以使其固定在链接中。 15-甲基 - 脱氧醚酚B和15-甲基疫霉素。第二阶段：该过程将用于大规模生产15-甲基鞭毛霉素，该过程将用于使酮底酸抗生素以足够量用于临床前和临床发育。 Kosan与R.W. Johnson Pharmaceutical Research Institute合作发现了酮酸酯铅，并期望将这种化合物或近距离模拟发展成为一种与该地区当前两名前跑者竞争的药物。拟议的商业应用：发现和开发可以克服抗药性机制的NOEL抗生素的需求越来越大。拟议的研究将产生改良的大环内酯类抗生素，这些抗生素有效地抵抗大花环抗性生物。由于全球大环内酯类抗生素的销售每年超过$ 3B，因此这些新的抗生素应具有显着的商业价值。