Investigation of polysaccharide translocation systems in Mycobacterium tuberculosis as potential novel drug targets
Tuberculosis (TB) affects a third of the worlds population and causes 1.7 million deaths annually. Mycobacterium tuberculosis, the causative agent of TB, has a unique cell envelope which accounts for its unusual low permeability and hence, contributes to resistance against common antibiotics (Alderwick et al. 2007). The main structural element consists of peptidoglycan, which is covalently attached to the arabinogalactan (AG), a complex polysaccharide that provides a molecular scaffold for long chain mycolic acids. There are certain aspects of mycobacterial cell wall biosynthesis that remain fragmented, particularly those associated with the translocation of large polysaccharide structures, such as AG, across the cytoplasmic membrane. We will use Mycobacterium smegmatis and Corynebacterium glutamicum as model systems to investigate the fundamental biochemistry of mycobacterial cell wall biosynthesis and assign functions to putative cell wall processing enzymes by generating conditional gene knock out (Alderwick et al., 2006; Birch et al., 2010). In addition, a range of biochemical and structural biology experimental approaches will be used to investigate the molecular mechanisms of these isolated recombinant proteins (Alderwick et al., 2011). Inhibition of cell wall biosynthesis remains a proven mechanism for mycobacterial chemotherapy, and with the advent of multi-dug and extensively-drug resistant TB, there has never been a greater need to identify new novel drug targets. The project outlined above will greatly assist our understanding of how this pathogen forms its impermeable barrier and provide new possibilities for the development of new therapies.
To find out more about studying for a PhD at the University of Birmingham, including full details of the research undertaken in each school, the funding opportunities for each subject, and guidance on making your application, you can now order your copy of the new Doctoral Research Prospectus, at: www.birmingham.ac.uk/students/drp.aspx
The School of Biosciences offers a number of UK Research Council (e.g. BBSRC, NERC) PhD studentships each year. Fully funded research council studentships are normally only available to UK nationals (or EU nationals resident in the UK) but part-funded studentships may be available to EU applicants resident outside of the UK. The deadline for applications for research council studentships is 31 January each year.
Each year we also have a number of fully funded Darwin Trust Scholarships. These are provided by the Darwin Trust of Edinburgh and are for non-UK students wishing to undertake a PhD in the general area of Molecular Microbiology. The deadline for this scheme is also 31 January each year.
All applicants should indicate in their applications how they intend to fund their studies. We have a thriving community of international PhD students and encourage applications at any time from students able to find their own funding or who wish to apply for their own funding (e.g. Commonwealth Scholarship, Islamic Development Bank).
The postgraduate funding database provides further information on funding opportunities available http://www.birmingham.ac.uk/postgraduate/funding/FundingFilter.aspx and further information is also available on the School of Biosciences website http://www.birmingham.ac.uk/schools/biosciences/courses/postgraduate/phd.aspx
Alderwick, L. J., et al. (2011). "The C-terminal domain of the Arabinosyltransferase Mycobacterium tuberculosis EmbC is a lectin-like carbohydrate binding module." PLoS pathogens 7(21383969): e1001299.
Alderwick, L. J., et al. (2007). "Structure, function and biosynthesis of the Mycobacterium tuberculosis cell wall: arabinogalactan and lipoarabinomannan assembly with a view to discovering new drug targets." Biochem. Soc. Trans 35(Pt 5): 1325-1328.
Alderwick, L. J., et al. (2006). "Arabinan-deficient mutants of Corynebacterium glutamicum and the consequent flux in decaprenylmonophosphoryl-D-arabinose metabolism." Glycobiology 16(11): 1073-1081.
Birch, H., et al. (2010). "A truncated lipoglycan from mycobacteria with altered immunological properties." Proceedings of the National Academy of Sciences of the United States of America 107(20133807): 2634-2639
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