Biosynthetic Engineering Approaches towards Generating New Tetracycline Antibiotics

这项由美国国家科学基金会颁发的生物技术、生化和生物质工程项目的奖项，支持理解和设计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。四环素是一种广谱抗生素，可有效治疗各种致病菌感染。然而，在过去的二十年中，四环素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，迫切需要通过开发这些天然产物抗生素的新类似物来克服耐药性。四环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了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。3)利用积累的知识来设计这些途径，以定制新的四环素类似物的生物合成。长期目标是结合代谢工程、蛋白质工程和生物合成工程来生产新的四环素，这些四环素可能提高抗生素抵抗病原体的活性。在这一建议中，PI将详细研究最近发现的两种复合物四环素的生物合成。该研究小组将专注于以以前未观察到的方式修饰四环素支架的酶。然后他们将使用这些酶来修饰临床上有用的四环素，如土霉素和二甲胺四环素。

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.