Monday, 4 April 2011

Structural Biology in the Fight against TB

About a third of the world's population - more than two billion people - are believed to be infected with Mycobacterium tuberculosis, the bacterium that, as its name implies, causes tuberculosis (TB). In most people the infection remains latent, but about 10% of cases develop into causes almost two million deaths a year. Strains of extensively drug-resistant TB (XDR-TB), which are resistant to two of the most effective first-line drugs and to at last three 0f the second-line drugs used against TB, have been found in many countries.

The Stop TB Partnership marks March 24 each year as World TB Day. 2011 is the second year of a two-year campaign to inspire innovation into TB research and care, On the move against tuberculosis. On March 24 2011 the Department of Biological Science at Birkbeck held an afternoon symposium featuring some of the department's tuberculosis research. This was organised by Dr Sanjib Bhakta, head of the ISMB Mycobacteria Research Laboratory and a senior lecturer in the department. Dr. Bhakta's research focuses on the discovery and validation of novel drug targets within the Mycobacterium tuberculosis proteome (link is to the TB proteome page in section 5 of PPS). Structural biology forms a crucial part of this work.

Birkbeck's Stop TB Day research symposium started with a keynote lecture given jointly by Dr Bhakta and Professor Edith Sim of Kingston University and the University of Oxford. Professor Sim is a member of the core group of TBD-UK, an organisation of UK researchers involved in the discovery and development of novel drugs for tuberculosis. After an introduction by Dr Bhakta, she described research in her group into the characterisation of a group of proteins that are necessary for the survival of the M. tuberculosis bacterium within cells. The enzyme NAT metabolizes and inactivates isoniazid, which is one of the first-line drugs used against TB. Researchers in Sim's group have developed inhibitors of this enzyme, some of which have been licensed to pharma company Eli Lilly for further development.

Sim's group is now focusing on a related family of proteins encoded by the Hsa genes which are involved in the metabolism of cholesterol and are also necessary for the bacterium to survive in macrophages. They have recently solved the structure of one of these enzymes, HsaD, which catalyses the cleavage of a carbon-carbon bond in one of the breakdown products of cholesterol. Structures of a mutant form of this enzyme alone (PDB code 2WUD) and with inhibitors (e.g. PDB code 2WUE) are yielding important insights into the mechanism of action of this enzyme. Both NAT and HsaD may prove useful targets for the design of anti-TB drugs that are likely to have novel mechanisms of action and that may therefore be active against resistant strains of the bacterium.

The keynote address was followed by some short talks by members of Dr Bhakta's research group at Birkbeck. Two of these, by Dimitrios Evangelopoulos and Dr Antima Gupta, described novel methods for testing drug susceptibility and for screening potential inhibitors respectively. Two others, however, focused again on the structural biology of potential drug targets. Dr Tulika Munshi described the Mur ligases, a family of proteins that are involved in synthesising the bacterium's complex cell wall. This cell wall is extremely rich in peptidoglycan; it is essential for the growth of Mycobacterium tuberculosis and has no homolog in the human proteome, both features that are important in a good drug target. Munshi and her colleagues have solved the structure of a member of this family, the ATP-dependent ligase MurE (PDB code 2XJA), in collaboration with Birkbeck structural biologist Professor Nicholas Keep (who is also the director of the MSc in Structural Molecular Biology) and identified amino acids that are essential for its activity. Another speaker, PhD student Juan David Gusman, described screening compounds recently isolated from Columbian plants as potential inhibitors of this enzyme. This work, published last year in the Journal of Antimicrobial Chemotherapy (link to PubMed) identified 3-methoxynordomesticine hydrochloride as a potential lead compound.

The scientific presentations were followed by a poster session and by an interesting panel discussion on some of the political issues involved in tackling this important public health issue. The take-home message from the day was that important steps are being taken - particularly in the academic and not-for-profit sectors - in elucidating the metabolism of this bacterium and developing badly needed treatments for the disease it causes and that Birkbeck researchers are playing an important part. If these treatments are to make it into clinical use, particularly in the developing world, however, political will as well as research insights will be needed.