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：生产对大环内酯类敏感和耐药细菌病原体具有强效抗菌活性的新型酮内酯抗生素。第一阶段：我们将开发一种生物工艺，通过 6-脱氧赤酮内酯 B 聚酮合酶的基因工程生产 15-甲基-6-脱氧赤酮内酯 B（15-甲基红霉素 A 的前体）。这将通过优化用于在天蓝色链霉菌（大肠杆菌的相关放线菌菌株）中制造目标化合物的底物的生物合成途径来实现。该底物将被工程化的 6-脱氧赤酮内酯 B 聚酮化合物合酶使用来制造 15-甲基-6-脱氧赤酮内酯 B，该底物将被红糖多孢菌菌株分离并生物转化为 15-甲基红霉素，或由工程化菌株直接生物转化为该化合物弗拉迪链霉菌 (Streptomyces fradiae)，含有产生 15-甲基-脱氧赤酮内酯 B 的基因和15-甲基红霉素。第二阶段：该工艺将针对 15-甲红霉素的大规模生产进行优化，15-甲红霉素将用于生产足量的酮内酯抗生素，用于临床前和临床开发。 Kosan 与 R.W. Johnson 药物研究所合作发现了一种先导酮内酯，并预计这种化合物或类似物将被开发成一种药物，与该领域当前的两种领先者竞争。拟议的商业应用：越来越需要发现和开发能够克服耐药机制的诺埃尔抗生素。拟议的研究将产生修饰的大环内酯类抗生素，可有效对抗大环内酯类耐药生物。由于大环内酯类抗生素的全球销售额每年超过 3B 美元，这些新型抗生素应该具有巨大的商业价值。