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Biosynthetic Engineering Approaches towards Generating New Tetracycline Antibiotics

生成新型四环素抗生素的生物合成工程方法

基本信息

批准号：
1033070
负责人：
Yi Tang
金额：
$ 32万
依托单位：
University of California-Los Angeles
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1033070&HistoricalAwards=false
关键词：
Biosynthetic Engineering Approaches towards Generating

项目摘要

This NSF award by the Biotechnology, Biochemical and Biomass Engineering program supports work to understand and engineer how important antibiotics are synthesized by microbial organisms. In particular, the PI and his research group are focusing on the group of compounds in the tetracycline family. Tetracyclines are broad-spectrum antibiotics that are effective towards the treatment of different pathogenic bacterial infections. However, overuse of tetracyclines in the last two decades has contributed to the emergence of bacterial resistance mechanisms that decreased the effectiveness of these drugs. Therefore, there is an urgent need to overcome the resistance by developing new analogs of these natural product antibiotics.Tetracyclines are synthesized by microorganisms via complex biosynthetic pathways. The goals of this project are to 1) understand how different tetracyclines are assembled by elucidating these underlying pathways; 2) dissect the basis of the enzymes that perform these chemical transformations.; and 3) use the accumulated knowledge to engineer these pathways towards tailored bio-synthesis of new tetracycline analogs. The long term goal is to combine metabolic engineering, protein engineering and biosynthetic engineering towards the production of new tetracyclines that may have improved antibiotic activities against resisting pathogens. In this proposal, the PI will examine the biosynthesis of two complex, recently discovered tetracyclines in detail. The research group will focus on the enzymes that decorate the tetracycline scaffolds in ways that were not observed before. They will then use these enzymes towards modifications of clinically useful tetracyclines such as oxytetracycline and minocycline.

生物技术，生物化学和生物质工程计划的NSF奖项支持了解和工程化微生物合成抗生素的重要性。特别是，PI和他的研究小组正在关注四环素家族中的化合物组。四环素类抗生素是广谱抗生素，对不同病原性细菌感染的治疗有效。然而，在过去的二十年中，四环素类药物的过度使用导致了细菌耐药机制的出现，降低了这些药物的有效性。因此，迫切需要开发新的天然产物类似物来克服耐药性。四环素类抗生素是由微生物通过复杂的生物合成途径合成的。这个项目的目标是：1）通过阐明这些潜在的途径来理解不同的四环素是如何组装的; 2）剖析进行这些化学转化的酶的基础。和3）使用积累的知识来设计这些途径，以定制新四环素类似物的生物合成。长期目标是将联合收割机、代谢工程、蛋白质工程和生物合成工程结合起来，以生产新的四环素类药物，这些药物可能对耐药病原体具有改善的抗生素活性。在本提案中，PI将详细研究两种最近发现的复杂四环素类药物的生物合成。该研究小组将专注于以前没有观察到的装饰四环素支架的酶。然后，他们将使用这些酶对临床有用的四环素如土霉素和米诺环素进行修饰。