Anti-Tuberculosis Agents from Natural Products: Molecular Characterisation of the Mode of Action
Lead Supervisor: Dr Sanjib Bhakta (Bbk)
Co-Supervisor: Professor Simon Gibbons (SoP)
Every second someone in the world is newly infected with Tuberculosis (TB) causing bacilli - Mycobacterium tuberculosis. Extensively drug resistant Tuberculosis (XDR-TB), a global health emergency, has highlighted the urgent need for the development of new drugs against the disease. Peptidoglycan is the polymeric mesh of the bacterial cell wall, which not only provides shape and structural integrity to the bacterial cell, but also plays a crucial role in protecting the bacteria against osmotic lysis and hydrolytic enzymes produced as a defence by macrophages. M. tuberculosis is unique in its peptidoglycan architecture indicating that inhibitors of the enzymes regulating the synthesis of the pivotal substrates are potential therapeutics against Tuberculosis.
The project will identify and characterise the anti-mycobacterial activity of natural products produced by plants. Active compounds will be isolated by chromatography and will undergo structure elucidation by high-field NMR spectroscopy, mass spectrometry and crystallography. A major part of the project will be to evaluate all the metabolites on growth, morphology, cell wall physiology and biochemistry using mycobacterial strains and their drug resistant mutants. The purified fractions will be assayed fro inhibition of ATP-dependent ligase activity and nature of inhibition will be characterised. A Structure Activity Relationship will be drawn from the results.
Applications are invited for a Bloomsbury Colleges funded PhD Studentship to be jointly supervised between Birkbeck College (Bbk) and the School of Pharmacy (SoP). The compound isolation and structure elucidation phases of the project will be conducted in the laboratory of Professor Simon Gibbons (SoP). The anti-mycobacterial evaluations including microbiology and chemical biology work will take place in the laboratory of Dr Sanjib Bhakta (ISMB/Bbk). This interdisciplinary project will give broad experience in mycobacterial physiology and biochemistry, anti-mycobacterial bioassays, modes of antibacterial action and mechanisms of drug resistance as well as experience in isolation chemistry and structure elucidation by spectral techniques.
Applications are welcome from students with a good first degree (minimum 2:! classification or equivalent) in microbiology, chemistry, biochemistry, pharmacy or any related subjects.
Key References
1. O'Donnell,G., Poeschl, R., Zimhony, O., Gunaratnan, M., Moreira, JBC., Neidle, S., Evangelopoulos, D., Bhakta, S., Malkinson, JP., Boshoff, HI., Lenaerts, A. and Gibbons, S. (2009) Bioactive pyridine-N-oxide disulphides from Allium stipitatum. J Nat Prod.
2. Madikane V.E., Bhakta S., Russell A.J., Campbell, W.E., Claridge, T.D., Elisha, B.G., Davies, S.G., Smith P., Sim, E. (2007) Inhibition of mycobacterial arylamine N-acetyltransferase contributes to anti-mycobacterial activity of Warburgia salutaris. Bioorg Med Chem.15(10): 3579-86.
3. Bhakta, S., Besra, G.S., Upton, A.M., Parish, T., Sholto-Douglas-Vernon, C., Gibson, K.J., Knutton, S., Gordon, S., DaSilva, R.P., Anderton, M.C., and Sim, E. (2004) Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target. J Exp Med 199: 1191-1199.
4. Methods in Molecular Medicine: Antibiotic Resistance Protocols. Edited by Gillespie, S.H. Human Press Towtowa New Jersey; Dimitrios Evangelopoulos and Sanjib Bhakta* (2009) Rapid assay for inhibitors.
Further details about the project may be obtained from:
Supervisor: Dr Sanjib Bhakta; s.bhakta.bbk.ac.uk
http://www.bbk.ac.uk/bcs/about_staff/bhakta
Co-Supervisor: Professor Simon Gibbons; simon.gibbons@pharmacy.ac.uk
http://www.pharmacy.ac.uk/simon_gibbons.html
Further information about PhDs at Birkbeck is available from:
http://www.bbk.ac.uk/study/phd/mphil-phddegrees/RPHBIOLG_RMPBIOLG.html;
http://www.bbk.ac.uk/crs/
Application forms and details about how to apply are available from:
http://www.bbk.ac.uk/study/pgform.pdf
Rhoda Elgar
Registry
Birkbeck, University of London
Malet Street
WC1E 7HX
Tel: 020 7631 6000
Closing date for the applications is 10 April 2009
