Principal Supervisor: Dr Helen O’Hare, Department of Infection, Immunity and Inflammation
Co-supervisor: Dr Galina Mukamolova
PhD project title: How do antibiotic-producing bacteria decide when to synthesise antibiotics, and how much to make?
University of Registration: University of Leicester
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