New Ketolide Antibacterial Drugs

长期目标：对大环内酯类敏感和耐药细菌病原体具有有效抗菌活性的新型酮内酯类抗生素的生产。第一阶段：我们将通过基因工程改造6-脱氧红霉素B聚酮合酶，开发生产15-甲基红霉素A前体15-甲基-6-脱氧红霉素B的生物工艺。这将通过优化用于在天蓝链霉菌（一种相关的大肠杆菌放线菌菌株）中制备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-脱氧红霉素B聚酮合酶用于制备15-甲基-6-脱氧红霉素B，该15-甲基-6-脱氧红霉素B将被分离并被多孢链霉菌菌株生物转化为15-甲基红霉素，或被含有生产15-甲基-脱氧红霉素B和15-甲基红霉素的基因的工程化的草莓链霉菌菌株直接生物转化为该化合物。第二阶段：该工艺将优化用于大规模生产15-甲基红霉素，其将用于制备足量的酮内酯类抗生素用于临床前和临床开发。Kosan与The R.W.合作发现了一种先导酮内酯。约翰逊药物研究所，并预计这种化合物或一种接近的类似物将被开发成一种药物，与目前这一领域的两个领跑者竞争。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。拟议的研究将产生改性的大环内酯类抗生素，对大环内酯类耐药微生物有效。由于大环内酯类抗生素的全球销售额每年超过30亿美元，这些新抗生素应该具有显著的商业价值。

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.