Abstract:
Natural products (NP) are small molecules that are made across all kingdoms of life. NPs provide producing organisms with beneficial traits, such as intra-species communication, nutrient acquisition, or growth inhibition of competing organisms. Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a major class of specialised metabolite. Almost all RiPPs originate from a precursor peptide that consists of an N-terminal leader sequence and a core peptide that is post-translationally modified into the final natural product. There is huge structural and functional diversity across the RiPP class, which includes antibiotics, hormones, signalling molecules and toxins, as well as thousands of uncharacterised RiPP biosynthetic gene clusters (BGCs). The thioamitides are a type of RiPP that have potent anticancer activity and I will discuss our progress in understanding the diversity, biosynthesis, and activity of these structurally complex molecules. The absence of a common biosynthetic feature across all RiPP pathways makes it difficult to identify novel RiPP BGCs, so I will also describe how we have developed strategies for the identification of RiPPs with novel chemical features, including the identification of a widespread RiPP family that lack canonical short precursor peptides. We use a combination of heterologous expression, genetics, in vitro pathway reconstitution, and detailed chemical analysis to understand the assembly of these new RiPP classes. These findings help to highlight the vast unexplored landscape of RiPP biosynthesis.