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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 producers of bioactive secondary metabolites including antibiotics, insecticides and immunosuppressants. Most of these are produced in tiny quantities, which is a significant barrier to developing and commercialisation of new molecules. Biosynthesis is controlled by complex regulatory systems, such that it only occurs under specific environmental conditions. Nutrient supply and growth arrest are two of the signals that can stimulate secondary metabolite production.

Recently we have identified a nutrient sensor in Mycobacterium tuberculosis that regulates central metabolism by activating a protein kinase. The sensor and kinase are widely conserved throughout the Actinobacteria. We have undertaken a proof of concept study showing that overexpression of the kinase substrate can increase antibiotic yield (BBSRC Natural Products Network). We aim to determine whether the sensory complex is fuctional in antibiotic-producing Streptomyces species and identify which nutrients (and other stimuli) stimulate kinase activity. The second aim is to determine how these signalling protein influence antibiotic production during fermentation.

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

Available to UK/EU applicants only
Application information
https://www2.le.ac.uk/research-degrees/doctoral-training-partnerships/bbsrc

References

A recent paper from our lab in a related area:
An Aspartate-Specific Solute-Binding Protein Regulates Protein Kinase G Activity To Control Glutamate Metabolism in Mycobacteria
https://mbio.asm.org/content/9/4/e00931-18

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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