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ISMB - Mycobacteria Research Laboratory

Academic Head: Dr Sanjib Bhakta, Senior Lecturer in Microbiology

Human infection with Mycobacterium tuberculosis was present in Egyptian and Peruvian mummies dating back as 600 BC1 (http://rspb.royalsocietypublishing.org/content/early/2009/09/29/rspb.2009.1484)

and at the end of the XIX Century, the disease took massive proportions specially in urban population where it was almost always a sentence of dead. After the discovery of the bacterial etiology of tuberculosis (TB) which led to a reliable diagnosis (still in use today) coupled to the introduction of the first antibiotics, it was though that the scourge was finally over. However in the last 20 years, the TB panorama has shown to be very complex and the World Health Organization declared TB to be a global health emergency in 1993, principally due to the emergence of drug-resistant strains (MDR  and XDR-TB) able to survive in the presence of anti-tubercular drugs, and HIV co-infection2 (http://www.springerlink.com/content/j765w62070x27408/).

Therefore there is a clinical need for novel chemical entities which must be potent enough for shortening the length of treatment and preventing the emergence of resistance, they must be safer than second-line drugs and they must not interfere with anti-retroviral therapies. In order to prevent cross resistance, the new drugs must act on novel targets on which the bacteria have never been attacked. These biochemical pathways need to be absent in mammalian organisms for the novel antimycobacterials to attain high selectivity.

In the ISMB-Mycobacteria Research Lab of the Department of Biological Sciences at Birkbeck, University of London, we are engaged in the discovery and validation of novel targets of Mycobacterium tuberculosis that may be exploited for developing novel chemical entities in order to fulfill the chemotherapeutic need. Our main interest involves the study of proteins performing essential functions in mycobacterial peptidoglycan biosynthesis and recycling3 (http://dx.doi.org/10.1016/j.tube.2009.10.007). We are also interested in establishing in vitro/ ex vivo models for testing growth inhibitors at different physiological states of the pathogen4-5 (http://jac.oxfordjournals.org/content/64/4/774.short) (http://www.springerprotocols.com/Abstract/doi/10.1007/978-1-60327-279-7_15). Several interesting small molecule hits have been discovered6-9 (http://dx.doi.org/10.1016/j.bmc.2007.02.011) (http://dx.doi.org/10.1021/np800572r) (http://jac.oxfordjournals.org/content/65/10/2101.abstract) (http://www.springerlink.com/content/c265460u467061t0/) and they constitute scaffolds for generating more potent anti-tubercular leads.

We grow, maintain and investigate both fast and slow growing mycobacterial species and their mutants in our specialized mycobacteria only safety containment level 1 and 2 GM laboratories with state of the art facilities including safety laminar air flow cabinets, standing, shaking, rolling mycobacterial culture incubators, gel documentation unit, refrigerated centrifuges, micro-centrifuges, CO2 cell culture incubator, stereo, compound, inverted microscopes with digital photography units and a networked computer, 40C, -200C, -80ºC fridge-freezers, Ribolyser, PCR machines and digital electro-transformation units.

An inter-disciplinary approach is required for attaining our goals and therefore we collaborate with an extensive group of scientists in UK and all around the world. We closely work with ISMB-Chemistry Labs, Biophysics Unit and Rosalind Franklin Laboratory for biochemical, biophysical characterization of mycobacterial proteins and protein crystallography respectively. We access Containment Level 3/4 Facilities at the Royal Free Hospital, UCL through an academic research contract in between UCL and Birkbeck, University of London. We represent as a core member group of Tuberculosis Drug Discovery Consortium, UK (http://www.tbd-uk.org.uk/) and affiliated member of the Centre for Infection, Immunity and Infection, Brunel University

Key interventions

  1. ATP-dependent Mur ligases are potential targets for novel anti-mycobacterial drugs (http://dx.doi.org/10.1016/j.tube.2009.10.007)
  2. SPOTi assay: A rapid and convenient method for evaluating TB growth inhibitors (http://www.springerprotocols.com/Abstract/doi/10.1007/978-1-60327-279-7_15)

Our research is externally supported by Medical Research Council, UK, Wellcome Trust, UK and Austrian Science Fund, EU.

Principal links

References

  1. Donoghue HD, Lee OY-C, Minnikin DE, Besra GS, Taylor JH, Spigelman M. Tuberculosis in Dr Granville's mummy: a molecular re-examination of the earliest known Egyptian mummy to be scientifically examined and given a medical diagnosis. Proceedings of the Royal Society B: Biological Sciences 2010;277:51-56.
  2. Friedland G. Tuberculosis, drug resistance, and HIV/AIDS: A triple threat. Current Infectious Disease Reports 2007;9:252-261.
  3. Basavannacharya C, Robertson G, Munshi T, Keep NH, Bhakta S. ATP-dependent MurE ligase in Mycobacterium tuberculosis: Biochemical and structural characterisation. Tuberculosis 2010;90:16-24.
  4. Gupta A, Bhakta S, Kundu S, Gupta M, Srivastava BS, Srivastava R. Fast-growing, non-infectious and intracellularly surviving drug-resistant Mycobacterium aurum: a model for high-throughput antituberculosis drug screening. J Antimicrob Chemother 2009;64:774-781.
  5. Evangelopoulos D, Bhakta S. Rapid methods for testing inhibitors of mycobacterial growth. Antibiotic Resistance Protocols, Methods in Molecular Biology: Humana Press, 2010. p. 279.
  6. Madikane VE, Bhakta S, Russell AJ, Campbell WE, Claridge TDW, Elisha BG, Davies SG, Smith P, Sim E. Inhibition of mycobacterial arylamine N-acetyltransferase contributes to anti-mycobacterial activity of Warburgia salutaris. Bioorganic & Medicinal Chemistry 2007;15:3579-3586.
  7. O’Donnell G, Poeschl R, Zimhony O, Gunaratnam M, Moreira JBC, Neidle S, Evangelopoulos D, Bhakta S, Malkinson JP, Boshoff HI, Lenaerts A, Gibbons S. Bioactive pyridine-N-oxide disulfides from Allium stipitatum. Journal of Natural Products 2008;72:360-365.
  8. Guzman JD, Gupta A, Evangelopoulos D, Basavannacharya C, Pabon LC, Plazas EA, Muñoz DR, Delgado WA, Cuca LE, Ribon W, Gibbons S, Bhakta S. Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis. Journal of Antimicrobial Chemotherapy 2010;65:2101-2107.
  9. Westwood I, Bhakta S, Russell A, Fullam E, Anderton M, Kawamura A, Mulvaney A, Vickers R, Bhowruth V, Besra G, Lalvani A, Davies S, Sim E. Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars. Protein and Cell 2010;1:82-95.

For information about the TB Drug Discovery Facility, please click here.

Mycobacteria Research Laboratory

Mycobacteria Research Laboratory

 
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