GENERATION OF KETOLIDES BY COMBINATORIAL BIOSYNTHESIS

通过组合生物合成生成酮内酯

• 批准号: 6015328
• 负责人: YONGQUAN XUE
• 金额: $ 10万
• 依托单位: ACERA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6015328
• 关键词: Streptomyces; antibiotics; biological products; combinatorial chemistry; enzyme activity; expression cloning; fatty acid synthase; molecular genetics; plasmids; protein biosynthesis; technology /technique development

The overall commercial aim of this project is to create new ketolide antiinfective agents using combinatorial biosynthesis technologies. The specific aims are: l) to develop a versatile plasmid-host expression system in Streptomyces venezuelae through which pikromycin analogues can be generated rapidly and systematically; and 2) generate novel ketolides by creating a 'hybrid biosynthetic pathway that combines the pikromycin polyketide synthase (PikA) with a cephamycin C non-ribosomal peptide synthetase domain. A key aspect of the proposed program involves refining a versatile expression system for engineered biosynthesis of complex polyketide natural products. This will provide plasmid- or chromosome-directed biosynthesis of the polyketide derived and aminosugar derived portions of the ketolide molecules. The development of this versatile set of molecular genetic tools will enable rapid generation of large numbers of ketolide structures for lead discovery of new antiinfective agents. Concurrent to the development of our molecular genetic tools, two specific hybrid biosynthetic pathways will be generated that introduce versatile molecular handles for creation of novel ketolide antibiotics. We expect this technology will provide a rapid source of novel ketolide molecules and structural templates for analysis in antimicrobial assay systems, and for further development using combinatorial chemistry or medicinal chemistry approaches. PROPOSED COMMERCIAL APPLICATIONS: The proposed research involves the development and reduction to practice of a technology that will provide rapid creation of new chemical entities for generation of novel pharmaceuticals with activity against drug-resistant pathogenic bacteria.

该项目的总体商业目标是利用组合生物合成技术创造新的酮类抗感染药物。具体目标是：1)在委内瑞拉链霉菌中开发一种多功能质粒宿主表达系统，通过该系统可以快速系统地生成比克霉素类似物；2)通过创建一个结合了猪霉素聚酮合成酶（PikA）和头孢霉素C非核糖体肽合成酶结构域的“杂交生物合成途径”，生成新的酮类化合物。该计划的一个关键方面涉及完善复杂聚酮天然产物工程生物合成的多功能表达系统。这将提供质粒或染色体定向生物合成的多酮衍生物和氨基糖衍生物的酮分子部分。这种多功能分子遗传工具的开发将使大量酮内酯结构的快速生成成为可能，从而有助于发现新的抗感染药物。在开发分子遗传工具的同时，将产生两种特定的混合生物合成途径，为创造新型酮类抗生素引入多功能分子手柄。我们期望这项技术将为抗菌检测系统的分析提供新的酮内分子和结构模板的快速来源，并为进一步使用组合化学或药物化学方法的开发提供帮助。拟议的商业应用：拟议的研究涉及开发和减少一种技术的实践，该技术将提供快速创建新的化学实体，用于生成具有抗耐药致病菌活性的新型药物。