Harnessing the biosynthetic potential of bacteria to produce ribosomally synthesised natural products

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Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a natural product class that have key ecological roles and significant clinical promise. Multiple RiPPs and their derivatives are used (or are in trials) in medicine, such as thiostrepton, nosiheptide, ziconotide, MOR107 and LFF571. RiPPs originate from a larger ribosomally synthesised precursor peptide that consists of an N-terminal "leader" sequence and a core peptide. The core peptide is post-translationally modified by tailoring enzymes and is then hydrolysed from the leader peptide to yield the mature RiPP.

Despite a requirement to be assembled from proteinogenic amino acids, there is huge structural diversity across the RiPP class. However, there are fundamental challenges associated with the computational identification of RiPP gene clusters, as RiPP biosynthetic pathways lack universally shared features. This contrasts to other natural product classes, whose pathways feature conserved enzymatic motifs that are used in their bioinformatic identification. Therefore, many RiPP gene clusters remain unknown. Recent genomics-led findings of completely new RiPP families with antibacterial, anticancer and antiviral activity highlights how decades of screening efforts have overlooked these important natural products.

To address the challenges associated with RiPP discovery, we developed RiPPER, which represents a new way to identify RiPP gene clusters. In this proposal, we will build on this research to develop tools and resources for the identification of new RiPP gene clusters. This will lead to RiPPER2, a tool that will be made freely available to the natural products community, therefore providing an informatic framework for the discovery of novel RiPPs. We will use microbial genetics, chemistry and biochemistry to characterise new RiPP families (discovered by RiPPER in preliminary work) that we predict will possess antibacterial activity.