About the Project
The Helge Dorfmueller (HD) lab is a young lab in the dynamic and vibrant Division of Molecular Microbiology. HD’s research focus lies on understanding the molecular details of how the human-exclusive pathogen Streptococcus pyogenes (GAS) synthesises an essential virulence factor. GAS is a severe burden to human life, causing a range of mild and severe, invasive infections with high morbidity and mortality rates (> 500,000 death / per year). The number of invasive strains increases worldwide. More than 1400 cases of invasive GAS infection were reported in the UK alone in 2013. These invasive infections have an associated fatality rate of 30% within less than 4 weeks [1]. Hypervirulent GAS strains emerge, increasing the demand for new potent treatments [1].
It is imperative that we identify and characterise new drug targets to develop more efficient antibiotics to obtain better treatments and to prevent a shortfall of antibiotics in the near future.
The HD lab investigates - in close collaboration with the lab from Prof. Mike Ferguson - the GAC biosynthesis pathway [2]. Functional and structural characterisation will be conducted to elucidate the catalytic mechanism of this novel virulence factor, to form the basis for future anti-virulence therapeutics.
The student will conduct fundamental and interdisciplinary research. The project and research training involves molecular microbiology and glycobiology, including cloning, protein expression and purification from recombinant bacterial system. Functional characterisation of the enzymes will be carried out using a combination of bacterial genetics, synthetic biology, carbohydrate analysis and enzyme assay development [3]. The student will have the opportunity to learn protein crystallisation and high-resolution single crystal X-ray diffraction analysis. These structural studies will reveal detailed insights into the mechanism of catalysis of these novel enzymes. Furthermore, the student will be trained in inhibitor screening to identify the first chemical compounds that bind to the target enzyme. We pair enzymology with structural biology to investigate the kinetic properties of these compounds, which in combination provide the full basis for future structure-based drug design [4].
References
References:
[1] Turner, C.E. et al. (2015); Emergence of a New Highly Successful Acapsular Group A Streptococcus Clade of Genotype emm89 in the United Kingdom. MBio. 6(4) :e00622
[2] van Sorge NM, et al. (2014); The classical Lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe.; 15(6):729-40. doi: 10.1016/j.chom.2014.05.009.
[3] van der Beek, S. L., Le Breton, Y., Ferenbach, A. T., Chapman, R.N., van Aalten, D.M.F., Navratilova, I., Boons, G.J., McIver, K., van Sorge, N. M. and H.C. Dorfmueller; 'GacA is Essential for Group A Streptococcus and Defines a New Class of Monomeric dTDP-4-dehydrorhamnose Reductases (RmlD)', in print at Molecular Microbiology.
[4] Dorfmueller, H.C., Borodkin, V.S., Schimpl, M., and van Aalten, D.M.F. (2009) 'GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation.' Biochem. J., 420(2), 221-7.
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