Award details

Development of New Gyrase Inhibitors by Combinatorial Biosynthesis (CombiGyrase)

Reference	BBS/E/J/0000A181
Principal Investigator / Supervisor	Professor Anthony Maxwell
Co-Investigators / Co-Supervisors
Institution	John Innes Centre
Department	John Innes Centre Department
Funding type	Research
Value (£)	181,567
Status	Completed
Type	Institute Project
Start date	01/01/2004
End date	31/12/2006
Duration	36 months

Abstract

The aim of this project is to generate novel inhibitors of gyrase and topoisomerase IV by engineering the biosynthetic pathways of potent natural inhibitors of these enzymes. The project will focus on antibiotics of the aminocoumarin type (novobiocin, clorobiocin, coumermycin A1, simocyclinones) and the cyclothialidine type (cyclothialidine and GR12222X). These compounds are produced by Streptomyces strains. The interaction of novobiocin, clorobiocin and the cyclothialidines with gyrase has been elucidated with biophysical and X-ray crystallographic methods by members of the consortium. The interaction of the simocyclinones, and of newly generated inhibitors, with gyrase and topoisomerase IV will be investigated. The results will be utilized for rational approaches for the development of new inhibitors by genetic engineering. The complete gene clusters involved in the biosynthesis of novobiocin, clorobiocin, coumermycin and simocyclinone have been cloned and sequenced by the members of this consortium; the biosynthetic gene cluster of cyclothialidine will be identified. Genes and operons within the clusters will be modified by gene inactivation, gene expression or gene replacement experiments within the natural producers. Furthermore, vectors containing entire biosynthetic gene clusters will be modified in E. coli and subsequently introduced into suitable Streptomyces host strains for production of novel metabolites. New molecules will also be generated by feeding specific strains with synthetic analogues of precursors. Accumulated compounds will be modified to generate an even wider array of new molecules. The biological activity of novel molecules will be assayed using enzyme assays, and antibacterial assays with human pathogens. Promising drug candidates will be investigated in animal infection models, pharmacological and toxicological data will be provided, and development of anti-infective drug candidates may be carried forward up to Phase I clinical trials.

Summary

unavailable

Committee	Closed Committee - Plant & Microbial Sciences (PMS)
Research Topics	X – not assigned to a current Research Topic
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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