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How do antibiotic-producing bacteria decide when to synthesise antibiotics, and how much to make?


About This PhD Project

Project Description

Actinobacteria are well-known as secondary metabolite producers and hence are of high interest commercially for drug discovery and for production of agrochemcials and human and animal therapeutics. They are common in in soil and aquatic environments where they play important roles in decomposition and nutrient cycling.

Most secondary metabolites are produces in tiny quantities, and developing routes to increase the yield of secondary metabolites is one of the most significant barriers to overcome both in discovery of new bioactive molecules and in development to commercialisation. Actinobacteria have sensory and regulatory systems to control production of secondary metabolites according to environmental conditions, and nutrient availability is one of the factors known to influence secondary metabolite production.

Recently we have shown that the pathogen Mycobacterium tuberculosis senses nutrients in its surroundings and regulates its central metabolism accordingly via a novel complex of sensory and regulatory proteins. These proteins are highly conserved throughout the Actinobacteria. The aim of this project is to confirm whether the sensory and regulatory functions are conserved in antibiotic producing Streptomyces species. The second aim is to investigate the influence of primary metabolism on the yield of secondary metabolites in naturally occurring antibiotic producers and industrially engineered antibiotic overproducers.

BBSRC Strategic Research Priority

Bioenergy and industrial biotechnology

Techniques that will be undertaken during the project

Genetic engineering of Streptomyces species to deliberately disrupt sensor and signalling proteins in order to manipulate metabolism.

Characterisation of the effects of genetic manipulation on metabolism by quantitative analysis of primary and secondary metabolites (by mass spectrometry-based metabolomics).

Determination of the specificity of Streptomyces sensor proteins by expression and purification of recombinant protein for ligand-binding assays and X-ray crystallography.

References

A recent paper from our lab in a related area:
PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006399

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