Investigation of Cyclic Peptide Natural Products: A Study of Biocatalysis and Mechanisms of Induction

Discovery of novel bioactive natural products (NPs) is critical, with approximately 66% of all known small molecule drugs stemming from NPs and many originating from the soil-dwelling bacteria, Streptomyces. Unfortunately, cryptic or silent biosynthetic gene clusters hinder access to novel bioactive NPs. Intriguingly, genomics suggests that there is a large reserve of unexplored biosynthetic gene clusters that likely encode production of novel NPs. Peptides, more specifically cyclic peptides, are a class of NPs with a plethora of bioactivities including anticancer, antibiotic, and antiviral activities. The work described here investigates peptide NPs from two angles. First, this project involves work towards the investigation of the substrate scope of a penicillin-binding protein type thioesterase, DsaJ. Second, the mechanism of induction of a small cyclic peptide is investigated through metabolomics studies. Ultimately, this work attempts to investigate the biosynthesis and inductive capabilities of cyclic peptides.