The Bloomsbury Colleges | PhD Studentships | Studentships 2012 | Natural and synthetic inhibitors of the Mur ligases: A promising target for novel anti-tuberculosis therapy
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Natural and Synthetic Inhibitors of the Mur Ligases: A Promising Target for Novel Anti-Tuberculosis Therapy

Lead Supervisors: Dr John Malkinson/Professor Simon Gibbons (School of Pharmacy)

Co-Supervisor: Dr Sanjib Bhakta (Birkbeck)

Tuberculosis (TB), caused by infection with bacteria belonging to the Mycobacterium tuberculosis complex, poses a major threat to global health. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains is a matter of grave concern and there is a desperate need for novel anti-TB agents to provide more effective therapeutic treatment.

This project will investigate the synthesis and isolation of natural product inhibitors of the Mur ligases, a family of enzymes that are pivotal for TB cell-wall biosynthesis. A combination of solution-phase and solid-phase approaches will be developed, firstly for the synthesis of the native substrates of these ligases, and ultimately for the synthesis of inhibitors. Such compounds will have therapeutic potential as novel anti-TB drugs. In parallel, we will also seek to isolate and identify natural products that have evolved in plants and which have demonstrated inhibition of the Mur ligases.

Synthetic and natural product inhibitors will be screened both for their ability to inhibit the growth of mycobacteria and also specifically for their inhibitory activity against the individual Mur ligase enzymes.

Requirements

The candidate must have a good first degree in either chemistry or a chemistry- or pharmacy-based science discipline. Sound chemistry knowledge and experience of synthesis are essential; knowledge/experience in carbohydrate and/or peptide chemistry would be an advantage. Research will be undertaken both at the School of Pharmacy (synthesis and isolation) and Birkbeck College (microbiology). The project offers an excellent opportunity to gain multi-disciplinary trainig and expertise and involves several of the key stages of modern drug discovery, directed towards a very significant and globally important disease target. Training will be provided in carbodydrate, peptide and solid-phase synthesis, the isolation and structure elucidation of bioactive natural products, and state-of-the-art mycobacterial molecular microbiology and bioassay.

Key References

Babic, A.; Pecar, S. Total synthesis of uridine diphosphate-N-acetylmuramoyl-L-alanine. Tetrahedron: Asymmetry 2008, 19, 2265-71.

Basavannacharya, C.; Robertson, G.; Munshi, T.; Keep, N.; Bhakta, S. ATP-dependent MurE ligase in Mycobacterium tuberculosis: biochemical and structural characterization. Tuberculosis (Edinb) 2010, 90, 16-24.

Basavannacharya, C.; Moody, P.R.; Munshi, T.; Cronin, N.; Keep, N.; Bhakta, S. Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis. Protein & Cell 2010, 1, 1011-22.

Evangelopolous, D.; Bhakta, S. Rapid methods for testing inhibitors of mycobacterial growth. Methods Mo. Biol.: Antibiotic Resistance Protocols 2010, 642, 193-201.

Guzman, J-D.; Wube, A.; Evangelopoulos, D.; Gupta, A.; Hufner, A.; Basavannacharya, C.; Rahman, M.M.; Thomaschitz, C.; Bauer, R.; McHugh, T.D.; Noveli, I.; Prieto, JmM.; Gibbons, S.; Bucar, F.; Bhakta, S. Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. J. Antimicrob. Chemother. 2011, 66, 1766-72.

Further details about the project may be obtained from:

Lead Supervisor: Dr John Malkinson, john.malkinson@pharmacy.ac.uk, http://www.pharmacy.ac.uk/john_malkinson.html

Co-Supervisor: Dr Sanjib Bhakta, s.bhakta@bbk.ac.uk, http://www.bbk.ac.uk/biology/our-staff/academic/sanjib-bhakta

Further information about PhDs at the School of Pharmacy is available from:

http://www.pharmacy.ac.uk/phd.html

Application forms and details about how to apply are available from:

http://www.pharmacy.ac.uk/apply_phd.html

If you have any questions, please email phd@pharmacy.ac.uk or contact the Registry on +44 (0)20 7753 5831

A list of supporting documents that must be included with your application can be found at http://www.pharmacy.ac.uk/apply_phd.html

This studentship is now closed.