Award details

Elucidating and engineering natural product biosynthesis in actinomycetes

Reference	BBS/E/J/000C0666
Principal Investigator / Supervisor	Dr Andrew Truman
Co-Investigators / Co-Supervisors
Institution	John Innes Centre
Department	John Innes Centre Department
Funding type	Research
Value (£)	223,844
Status	Completed
Type	Institute Project
Start date	01/10/2013
End date	31/03/2017
Duration	41 months

Abstract

My research encompasses the discovery, characterisation and engineering of pathways that make drug-like molecules in actinomycete bacteria. I am particularly interested in bioactive natural products that also possess unusual structural features. We employ a "gene to product" approach, which requires a wide variety of techniques, such as the computational analysis of bacterial genomes, the genetic manipulation of gene clusters and the in vitro analysis of pathway proteins. Two major routes to peptide natural products have evolved: non-ribosomal peptide synthetases (NRPSs) and ribosomally synthesized and post-translationally modified peptides (RiPPs). We study the biosynthesis of complex metabolites produced by both types of pathway. NRPSs are massive multi-domain assembly line proteins and are responsible for the biosynthesis of the glycopeptide antibiotics. These hugely complex molecules are used as drugs of last resort to treat aggressive methicillin-resistant Staphylococcus aureus (MRSA) infections. Through a variety of collaborations, I am investigating the regulation, activity and biosynthesis of these molecules. In contrast to NRPSs, RiPPs originate from ribosomal precursor peptides. Bottromycin is a clinically promising and structurally unique RiPP, and is active towards multi-drug resistant bacteria, such as MRSA. Its structurally novelty makes it a promising lead compound in the fight against infection. Following the discovery of the bottromycin pathway in Streptomyces scabies, we are now characterising the enzymatic steps of this pathway to determine how structural complexity is introduced into this compound. Additional work on this pathway includes mutagenesis to produce novel derivatives and an analysis of the regulatory factors that control bottromycin biosynthesis. This research will inform future investigations into other novel RiPP pathways.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Microbiology, Pharmaceuticals, Synthetic Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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