Prof. Peter L. Roach – University of Southampton
Dr. Andrew Lawrence – University of Kent
Prof. Petra C. F. Oyston – DSTL Porton Down
Microbes produce a wide range of complex natural products, with a wide variety of biological functions.
Some of the most useful natural products are antibiotics, including the clinically important aminoglycosides and carbapenems. These are produced through intricate biosynthetic pathways. We will explore the potential of using microbial cells to function as factories for the improved biosynthesis of these antibiotics, and explore the potential of novel exogenous enzymes to yield new or modified antibiotic frameworks.
i) Optimise production cell types to cope with high antibiotic concentrations.
ii) Investigate the use of novel enzymes to modify the core structures of antibiotics or their biosynthetic intermediates, generating novel antibiotic frameworks.
iii) Investigate biosynthetic enzymes – in particular those catalysing difficult or unusual transformations.
iv) Optimise the yields of antibiotic production by in cellulo systems and using expressed enzymes in cell lysates.
This interdisciplinary project will use a wide range of practical approaches, such as molecular biology to construct polycistronic systems to coexpress biosynthetic enzymes and to develop genetically modified strains for improved robust antibiotic production. In addition, using enzyme mediated reactions, we will generate modified alternative reaction products. These novel antibiotics will be chemically characterised using HPLC purification, HPLC-MS analysis and NMR analysis; their potency as antibiotics against a range of microorganisms will be measured during a placement at DSTL.
The project spans synthetic biology, biochemistry and microbiology: a broad training will be provided in molecular biology, microbiology, protein purification, enzymology, structural biology and chemical characterisation of complex antibiotics. The successful candidate will be expected to spend time at both universities (Southampton and Kent) and a placement at DSTL.