Antibiotic Gene Clusters

说明(申请人提供)：在药物开发的临床试验阶段和商业化阶段都需要对工业微生物进行菌种改良。尽管菌株改良在降低药品生产成本方面发挥了巨大的经济作用，但这种作用通常没有得到公众的认可，除非在国家危机期间，药物需求可能会飙升。第一次这样的危机涉及第二次世界大战期间青霉素的生产。未来的危机可能涉及对抗生物恐怖袭击所需的药物。遗憾的是，自20世纪40年代S以来，用于菌株改良的经验遗传方法并没有实质性的改进。现代基因工程技术为开发更新的合理方法提供了希望，但还需要更多的基础研究。这项研究不再受到制药业的严格追捧。在这个项目的第一阶段，我们通过克隆和测序一个新的红霉素基因簇，极大地拓宽了我们对红霉素产生的遗传学的理解。在第二阶段，我们建议将这一新的基础知识应用于红霉素和其他重要药物菌株改良的现代方法的开发。

DESCRIPTION (provided by applicant): Strain improvement of industrial microorganisms is required at both the clinical testing stage and commercialization stage of drug development. Although strain improvement plays an enormous economic role in reducing the costs of pharmaceutical manufacturing, this role is generally unrecognized by the public, except during a national crisis when demand for a drug may soar. The first such crisis involved the production of penicillin during World War II. Future crises may involve drugs needed to counter bio-terrorist attacks. Unfortunately, the empirical genetic methods used for strain improvement have not substantially improved since the 1940's. Modern genetic engineering technology offers hope that newer rational methods can be developed, but more basic research is required. This research is no longer being rigorously pursued by the pharmaceutical industry. In Phase I of this project we significantly broadened our understanding of the genetics of erythromycin production by cloning and sequencing a new erythromycin gene cluster. In Phase II we are proposing to apply this new basic knowledge to the development of modern methods of strain improvement for erythromycin and other important drugs.