Harnessing Natural Product Biosynthetic Pathways for Novel Discovery Platforms

Abstract

Natural products offer exceptional chemical diversity and bioactivity, yet discovery efforts have slowed due to high rediscovery rates and limited access to novel scaffolds. This thesis presents two strategies to reinvigorate discovery: genome mining for tetrahydroisoquinolines (THIQs) and development of photometabolomics for identifying light-reactive natural products. Chapter 2 detailed genome mining using the SfmC module from saframycin A biosynthesis to identify nine candidate strains. Multiplexed activity profiling revealed DNA damage and apoptosis responses consistent with THIQ bioactivity, supporting the use of biosynthetic gene-guided mining and multiplexed activity profiling for prioritizing strains. Chapter 3 introduced photometabolomics, a method for detecting light-sensitive compounds by comparing LC-MS profiles of dark and light-treated extracts. Ciromicin A and B served as a model system, demonstrating photoisomerization. A prototype photoreactor was designed to standardize exposure conditions. Multiplexed activity profiling of candidate strains revealed light-dependent responses in two extracts derived from Nocardia tenerifensis. This work lays the foundation for future efforts to isolate new THIQs, explore photoisomer bioactivity, and refine photometabolomics into a high-throughput discovery platform.