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Understanding and Exploiting Tunicamycin (Bio)Synthesis to Enable Novel Antibiotics and Inhibitors

Reference	BBS/E/J/000CA488
Principal Investigator / Supervisor	Professor Mervyn Bibb
Co-Investigators / Co-Supervisors
Institution	John Innes Centre
Department	John Innes Centre Department
Funding type	Research
Value (£)	55,982
Status	Completed
Type	Institute Project
Start date	13/08/2012
End date	12/08/2015
Duration	36 months

Abstract

Tunicamycin inhibits bacterial cell wall biosynthesis by blocking MraY, the enzyme that makes the essential biosynthetic precursor lipid I. This mode of action is different to that of any clinically used antibiotic, and the compound is thus active against a broad range of antibiotic resistant bacterial pathogens. Unfortunately, tunicamycin also inhibits protein N-glycosylation, and is thus toxic to mammals. These two inhibitory activities are believed to reflect different structural characteristics of tunicamycin. We have recently, through genome mining of the producing organism Streptomyces chartreusis, discovered the gene cluster for tunicamycin biosynthesis. We have also developed methods for synthesizing key biosynthetic intermediates. We will explore not only the mechanism of formation of the unique tunicamycin structure but also assess the utility of the biosynthetic enzymes to generate novel tunicamycin derivatives. The modular structure of tunicamycin suggests that the inhibitory scaffold may be altered in a systematic way to tune its activity towards and away from the two existing targets. Early results have confirmed that core scaffold modules are active against other nucleotidyl-dependent enzymes. This suggests that analogues may be created that could uncouple existing activities, perhaps allowing eventual use as lead compounds for therapy. This collaborative project will explore tunicamycin biosynthesis, producer immunity, the enzymology (and structures) of key tunicamycin biosynthetic enzymes, the synthesis of tunicamycin analogues, and their activity in screens against target organisms and enzymes

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Industrial Biotechnology, Microbiology, Pharmaceuticals, Structural 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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