ENGINEERED BIOSYNTHESIS OF NOVEL KETOLIDE COMPOUNDS

酮内酯是由红霉素制备的半合成大环内酯类化合物，具有 最近出现了治疗几种疾病的有希望的药物 临床上重要的抗药性细菌，包括 疑似胃癌病原体幽门螺杆菌。的长期目标是 这个项目是生成一个基于酮内酯的分子库 使用由Kosan和其他人开发的新技术的化合物类。 这项技术被称为组合生物合成，允许人们改变 并通过基因操作构建新型聚酮产品 聚酮合成酶(PKS)生物合成这种丰富的 具有药理活性的化合物。具体地说，红霉素PKS 将被改造成在体内产生酮内酯中间体 目前是从复杂的合成策略中衍生出来的。一个重要的 这种方法的优点是能够操纵结构 通过标准技术无法获得的酮内酯的特征。 最终，一些结构不同的酮内酯中间体将 具有预期的抗幽门螺杆菌和其他 具有抵抗力的生物。 第一阶段将包括对红霉素PKS进行工程，以生产 酮内酯中间体。两种突变将由体内的 重组策略，由此产生的PKS将被表达为 特制的链霉菌宿主/载体系统。 建议的商业应用：这项研究应该导致 为应对日益严重的耐药性问题而开发的化合物 有机体。In为进一步发展一部小说提供了机会 具有广泛应用前景的铅化合物生产技术 临床靶点的多样性。

The ketolides, semisynthetic macrolides prepared from erythromycin, have recently emerged as promising drugs for the treatment of several clinically important antibiotic resistant bacteria, including the suspected gastric cancer agent Helicobacter pylori. The long term goal of this project is to generate a library of molecules based on the ketolide class of compounds using a novel technology developed by Kosan and others. This technology, termed combinatorial biosynthesis, allows one to alter and construct novel polyketide products by genetically manipulating the polyketide synthases (PKSs) which biosynthesize this rich source of pharmacologically active compounds. Specifically, the erythromycin PKS will be engineered to produce, in vivo, a ketolide intermediate which is currently derived from a complicated synthetic strategy. An important advantage to this approach is the ability to manipulate structural features of ketolides which are inaccessible through standard techniques. Ultimately, a number of structurally diverse ketolide intermediates will be produced with anticipated activity against H. pylori and other resistant organisms. Phase I will consist of engineering the erythromycin PKS to produce a ketolide intermediate. Two mutations will be introduced by an in-vivo recombination strategy, and the resulting PKS will be expressed ina specially constructed Streptomyces host/vector system. PROPOSED COMMERCIAL APPLICATION: This research should lead to the development of compounds to combat the growing problem of drug resistant organisms. In provides the opportunity to further develop a novel technology with broad application for producing lead compounds against a variety of clinical targets.