Genome-led discovery of novel RiPP natural products

Russell, Alicia (2020) Genome-led discovery of novel RiPP natural products. Doctoral thesis, University of East Anglia.

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Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural product that display a range of clinically relevant bioactivities such as antimicrobial and anticancer. The full extent of RiPP biochemical complexity has not yet been fully explored. This is partly due to challenges associated with genome mining for RiPP biosynthetic gene clusters (BGCs), which is often hampered by poor detection of the short precursor peptides that are ultimately modified into the final metabolite. Microorganisms are therefore predicted to produce many more RiPPs than are currently known.

In this thesis, a novel RiPP genome mining tool, RiPPER, is employed to identify novel RiPP precursor peptides near YcaO-domain proteins, enzymes that catalyse various RiPP post-translational modifications including heterocyclisation and thioamidation. From this analysis, I report the identification of a novel and diverse family of RiPP BGCs present in over 230 species of Actinobacteria and Firmicutes.

A representative BGC from Streptomyces albus J1074 was characterised through cloning and expression of the pathway followed by genetic, metabolomic and structural studies. I thus report the identification of a novel RiPP, streptamidine, which contains a structurally rare amidine ring. The identification of this metabolite along with bioinformatic analysis of homologous pathways suggests that amidine-containing RiPPs might be widespread in nature, where previously only two examples have been characterised. Bottromycin and klebsazolicin are both antibiotic RiPPs whose activity has been attributed to their amidine rings. Amidines might therefore represent an important structural feature for antibiotics that can be explored in the future.

Overall, these studies show that many more biochemically diverse natural products can be discovered through the use of targeted genome mining approaches, even in widely studied model organisms such as Streptomyces albus J1074. This represents an exciting prospect for the future of antimicrobial discovery.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 19 Oct 2021 08:46
Last Modified: 31 Oct 2021 00:39

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