Engineering Bacterial Cell Factories for Natural Product Biosynthesis

Bacteria are invaluable sources of natural products with pharmaceutical and industrial relevance, owing to the remarkable diversity of the bioactive compounds and chemical structures they can synthesize. In recent years, significant advances have been made to unlock the biosynthetic potential of bacteria. Notably, progress in more accessible genome sequencing, combined with sophisticated bioinformatics has substantially expanded our ability to identify bacterial biosynthetic gene clusters (BGCs) responsible for the production of these secondary metabolites. In this thesis, several bottlenecks in the discovery and production of natural products from bacteria were identified, and some approaches to enable access to them are presented. These include novel strategies from the perspectives of genome sequencing, genome mining, genetic engineering, and metabolic engineering. This thesis encompasses exploring the biosynthetic potential of bacteria, identifying novel BGCs, adapting strategies to modify BGCs for heterologous expression, and optimizing the precursor supply for the biosynthesis of bacterial natural products.