Award details

Analysis and exploitation of genes for type B antibiotic biosynthesis

Reference	BBS/E/J/00001223
Principal Investigator / Supervisor	Professor Mervyn Bibb
Co-Investigators / Co-Supervisors
Institution	John Innes Centre
Department	John Innes Centre Department
Funding type	Research
Value (£)	19,045
Status	Completed
Type	Institute Project
Start date	02/01/2000
End date	05/05/2002
Duration	28 months

Abstract

Streptomycetes are Gram-positive mycelial soil bacteria that produce about 70% of all known antibiotics, including many with important applications in human medicine and in agriculture. Despite the success of the pharmaceutical industry, the need for knowledge-based improvements in antibiotic productivity and for the development of new antibiotics remains. This can only be accomplished with an increased understanding of how antibiotic biosynthesis occurs, and of how the process is regulated. Streptomycetes form highly differentiated colonies consisting of a branched network of vegetative substrate mycelium and specialised aerial hyphae that ultimately develop into spores. Antibiotic production in these organisms occurs in a growth phase-dependent and tissue-specific manner, with synthesis limited to the substrate mycelium. We have identified four small diffusible signalling molecules in culture supernatants of transition phase cultures of Streptomyces coelicolor A3(2) that elicit precocious antibiotic production by the wild-type strain. One of these, ScbI, is a gamma-butyrolactone which is active in nanomolar concentrations. We aim to elucidate the mechanism whereby these signalling molecules determine the onset of antibiotic production. We will determine the structures of the three remaining factors, and assess whether they act as indicators of cell density (quorum sensors), or are synthesized in response to other physiological signals (e.g. nutrient limitation). We will analyze the role of pleiotropic regulatory genes for antibiotic production in ScbI synthesis in an attempt to define a regulatory cascade for gamma-butyrolactone production. We will analyze a recently identified cluster of genes for their role in gamma-butyrolactone synthesis and perception, and in antibiotic production. We will determine whether the gamma-butyrolactone acts as a co-activator or inducer of antibiotic synthesis by analyzing the role of its likely binding protein (ScbR) in antibiotic production, and we will attempt to identify the genes directly under the control of ScbR. We will attempt to develop an in vitro system for the biosynthesis of ScbI that will elucidate how the compound is made in vivo. Techniques used include molecular genetics, physiology, biochemistry, mass spectrometry, NMR and circular dichroism, and comprise an integrated approach to the analysis of how these signalling molecules determine the onset of antibiotic production, and their possible role in morphological differentiation, in the genetically characterized and manipulable S. coelicolor.

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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