Biosynthetic Engineering Approaches towards Generating New Tetracycline Antibiotics

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

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.