UC Santa Cruz

Natural products are secondary metabolites produced from a variety of organisms found in nature that have been and continue to be a rich source for a wide range of therapeutics playing a key role in drug discovery. They are also an abundant source of structurally complex and diverse molecules that can be difficult to imagine and achieve through combinatorial chemistry alone. Exploring the depth of natural product biosynthesis studies has opened up new avenues in the field of natural products from our understanding of chemistry, protein function and dynamics, and genetic regulation, which aid in the development of drugs and chemical tools. It is well known that the biosynthesis of natural products is primarily carried out by a series of protein catalysts encoded in the genome, however, a small but growing number of molecules involve one or more protein independent or non-enzymatic steps. As we continue to build a strong foundation of how microbes and higher organisms produce natural products, therein lies a need for understanding how non-enzymatic biosynthetic steps occur. Presented here is the development of a nuclear magnetic resonance (NMR)-based discovery platform to identify natural products scaffolds that can undergo non-enzymatic reactions in microbial cultures and the investigation of the non-enzymatic formation of the tricrilactone family of natural products through biomimetic synthesis. Separately, this thesis also discusses the re-isolation of aborycin, a tricyclic lasso peptide, from a Streptomyces sp. and its biological evaluation against Type III Secretion System (T3SS) in Pseudomonas aeruginosa. This is the first report to date of aborycin as an effective T3SS inhibitor.