Research Theme within School of Biosciences: Molecular and Cell Biology
We (GSB) have contributed over the past several years in understanding the characteristics of the cell wall of TB, which has been the site of action of a number of front-line TB agents. We have now opted for a broader strategy: identification of new drug targets and drug development (with Professor Minnikin); vaccine development; identification of mechanisms of intracellular survival, replication and pathogenesis; definition of the fundamental genome of the tubercle bacillus, its phenotype and the functionality of the phenotypic characteristics through derivation of mutants.
It is a widely held view that efforts to relieve the disease burden imposed by tuberculosis must benefit from concerted attempts to understand the basic biochemistry of the organism, particularly in view of the current availability genomic data from the M. Tuberculosis genome. Thus, providing a timely insight into these remarkable bacteria and several novel areas of mycobacterial cell wall physiology
The cell wall of Mycobacterium tuberculosis: A focus for new drug targets and vaccines
There has been no significant decrease in worldwide mortality due to tuberculosis (TB) since before the time of Koch; the advent of sanatoria and chemotherapy, which drastically reduced TB in the more developed countries, has had no profound effect on the global problem. The reasons for the transient increase have been well documented: the HIV/AIDS epidemic, increased immigration and transmission from high-prevalence countries, and the emergence of multi-drug resistant strains of TB.
I am internationally recognised for my work in Mycobacterium tuberculosis cell wall physiology. I have contributed to many areas of this field including, microbial pathogenesis, mechanisms of antibiotic resistance and drug development. More specifically, I have been involved in the structural elucidation of a number of glycolipids from mycobacteria, such as the phenolic glycolipid of M. haemophilum; the acylated trehaloses of M. tuberculosis H37Rv; the lipooligosaccharides from M. gordonae and the glycopeptidolipids of M. xenopi and M. senegalense. I have extended our knowledge of the mycolyl-arabinogalactan complex from M. tuberculosis and have obtained a more sophisticated impression of the primary and secondary relationship of these entities.
More recently, my research interests have also included:
i) the biosynthesis and molecular basis of mycolic acids, glycoproteins, and the complex polysaccharides, arabinogalactan and lipoarabinomannan, which has resulted in the development of new acyltransferase and glycosyltransferase assays, and the identification of key intermediates and characterisation of new products resulting from enzymic synthesis;
ii) the isolation and molecular characterisation of M. tuberculosis cell wall mutants, generated through either chemical or genetic means, which has allowed me to evaluate the role of various cell wall structures as virulence determinants;
iii) the mode of action of anti-tuberculosis drugs, such as isoniazid, ethionamide, thiolactomycin and ethambutol, which has resulted in the identification of resistance genes and the structural elucidation of secondary metabolites;
and finally iv) the synthesis of custom-designed antagonists against M. tuberculosis. For instance, one of my early key achievements, which was ground-breaking in this area of research, was published in Science:the identification of the major excreted protein antigen [antigen 85] as a key mycolyltransferase enzyme involved in the biogenesis of the cell wall of M. tuberculosis.
In a second research strand, I have been at the forefront in the discovery of M. tuberculosis T-cell antigens and the CD1 antigen presentation pathway. For instance, the initial identification of glucose monomycolate (GMM) as a CD1b-presented glycolipid and its precise structural requirements, antigen processing and presentation to CD1b-restricted T cells were key discoveries published in Science, EMBO J. and Nature Immunology.
More recently, I have described in ground-breaking articles published in Nature and Journal of Experimental Medicine that the T-cell antigen receptor, CD1c protein-mediated recognition is governed by a family of M. tuberculosis glycolipids. My research continues to extend significantly the state of the art in both research areas. At the same time I have bridged several research disciplines to set the research agenda in the biosynthesis of the mycobacterial cell wall and the CD1 field, which is evidenced by the quality of my internationally refereed papers, significant funding in the form of several long-term Programme Grants, and ability to attract first-rate international Research Fellows and PhD students.
My research has also been recognised by the award of several prizes (e.g. the W.H. Pierce Memorial Prize from the Society for Applied Microbiology; the Carbohydrate Chemistry Award from the Royal Society of Chemistry; Royal Society Wolfson Research Merit Award; the internationally prestigious Biochemical Society Award), and numerous plenary lecture invitations (e.g. Keystone Research Conferences)
Batt, S.M., T. Jabeen, V. Bhowruth, L. Quill, P.A. Lund, L. Eggeling, L.J. Alderwick, K. Fütterer, and G.S. Besra (2012) Structural basis of inhibition of M. tuberculosis DprE1 by benzothiazinone inhibitors. Proceedings of the National Academy of Sciences USA 109: 11354-11359.
Jervis, P., L.M. Graham, E.L. Foster, L.R. Cox, S.A. Porcelli, and G.S. Besra (2012) New CD1d agonists: synthesis and biological activity of 6’-triazole-substituted a-galactosyl ceramides. Bioorg. Med. Chem. Lett. 22: 4348-4352.
Detre, C., M. Keszei, N. Garrido-Mesa, K. Kis-Toth, W. Castro, A.F. Agyemang, N. Veerapen, G.S. Besra, M.C. Carroll, G.C. Tsokos, N. Wang, E.A. Leadbetter, and C. Terhorst (2012) SAP expression in invariant NKT cells in requisite for cognate help and dispensable for non-cognate support to B cells. Blood. 120: 122-129.
Speak, A.O., N. Platt, M. Salio, D.T. Vruchte, D.A. Smith, D. Shepherd, N. Veerapen, G.S. Besra, N.M. Yanjanin, L. Simmons, J. Imrie, J.E. Wraith, R. Lachmann, R. Hartung, H. Runz, E. Mengel, M. Beck, C.J. Hendriksz, F.D. Porter, V. Cerundolo, and F.M. Platt (2012) Invariant Natural Killer T cells are not affected by lysosomal storage in pateinets with Niemann-Pick disease type C. Eur. J. Immunol. 42: 1886-1892.
Mishra, A.K., K. Krumbach, D. Rittman, S. Batt, O.Y. Lee, S. De, J. Frunzke, G.S. Besra, and L. Eggeling (2012) Deletion of manC in Corynebacterium glutamicum results in a phospho-myo-inositol mannoside and lipoglycan deficient mutant. Microbiology. 158: 1908-1917.
Varela, C., D. Rittmann, A. Singh, K. Krumbach, K. Bhatt, L. Eggeling, G.S. Besra*, and A. Bhatt (2012) MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol. 19(4): 498-506. [*co-corresponding author].
Woude, van der A.D., D. Sarkar, A. Bhatt, M. Sparrius, S.A. Raadsen, L. Boon, J. Geurtsen, A.M. van der Sar, J. Luirink, E.N. Houben, G.S. Besra, and W. Bitter (2012) An unexpected link between lipooligosaccharide biosynthesis and surface protein release in Mycobacterium marinum. J. Biol. Chem. 287: 20417-20429.
Wu, L., V.V. Parek, C.L. Gabriel, D.P. Bracy, P.A. Marks-Shulman, R.A. Tamboli, S. Kim, Y.V. Mendez-Fernandez, G.S. Besra, J.P. Lomenick, B. Williams, D.H. Wasserman, and L. van Kaer (2012) Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc. Natl. Acad. Sci. USA. 109 (19): E1143-1152.
Usha, V., J.V. Hobrath, S.S. Gurcha, R.C. Reynolds, and G.S. Besra (2012) Identification of novel Mt-Guab2 inhibitor series active against M. tuberculosis. PLoS ONE 7(3): e33886.
Jervis, P.J., M. Moulis, J.P. Jukes, H. Ghadbane, L.R. Cox, V. Cerundolo, and G.S. Besra (2012) Towards multivalent CD1d ligands: synthesis and biological activity of homodimeric a-galactosyl ceramide analogues. Carbohydr. Res. (2012) 356: 152-162.
Usha, V., A.J. Lloyd, A.L. Lovering, and G.S. Besra (2012) Structure and function of Mycobacterium tuberculosis meso-diaminopimelic acid (DAP) biosynthesis enzymes. FEMS Microbiol. Lett. 330(1): 10-16.
Leon, L., R.V. Tatituri, R. Grenha, Y. Sun, D.C. Barral, A.J. Minnaard, V. Bhowruth, N. Veerapen, G.S. Besra, A. Kasmar, W. Peng, D.B. Moody, G.A. Grabowski, and M. B. Brenner (2012) Saposins utilize two strategies for lipid transfer and CD1 antigen presentation. Proc. Natl. Acad. Sci. USA 109(12): 4357-4364.
Jankute, M., S. Grover, A.K. Rana, and G.S. Besra (2012) Arabinogalactan and lipoarabinomannan biosynthesis: structure, biogenesis and their potential as drug targets. Future Microbiol. 7(1): 129-147.
Wojno, J., J.P. Jukes, H. Ghadbane, D. Shepherd, G.S. Besra*, V. Cerundolo, and L.R. Cox (2012) Amide analogs of CD1d agonists modulate iNKT cell-mediated cytokine production. ACS Chem. Biol. 7: 847-855 [*co-corresponding author]
King, I.L., A. Fortier, M. Tighe, J. Dibble, G. F.M. Watts, N. Veerapen, A.M. Haberman, G.S. Besra, M. Mohrs, M.B. Brenner, and E.A. Leadbetter (2011) iNKT cells direct B cell responses to cognate lipid antigen in an interleukin 21-dependent manner. Nat. Immunol. 13(1): 44-50.
Cohen, N.R., R.V.V. Tatituri, A. Rivera, G. Watts, A. Chiba, G.S. Besra, E.G. Pamer, M. Brigl, and M.B. Brenner (2011) Innate recognition of cell wall b-glucan via Dectin-1 drives iNKT cell responses against fungi. Cell Host & Microbe, 10(5): 437-450.
Patel, O., D.G. Pellicci, A.P. Uldrich, L.C. Sullivan, M. Bhati, M. McKnight, S.K. Richardson, A.R. Howell, T. Mallevaey, J. Zhang, R. Bedel, G.S. Besra, A.G. Brooks, L.K. Nielsen, J. McClusky, S.A. Porcelli, L. Gapin, J. Rossjohn, and D.I. Godfrey (2011) Vb2 Natural killer T cell receptor mediated recognition of CD1d-glycolipid antigen. Proc. Natl. Acad. Sci. USA, 8(47): 19007-19012.
Kinjo, Y., P. Illarionov, J.L. Vela, B. Pei, E. Girardi, X. Li, Y. Li, M. Imamura, Y. Kaneko, A. Okawara, Y. Miyazaki, A. Gomez-Velasco, P. Rogers, S. Dahesh, S. Uchiyama, A. Khurana, K. Kawahara, H. Yesilkaya, P.W. Andrew, C-H Wong, K. Kawakami, V. Nizet, G.S. Besra, M. Tsuji, D.M. Zajonc, and M. Kronenberg (2011) Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat. Immunol. 12: 966-974.
Muppidi, J.R., T.I. Arnon, Y. Bronevetsky, N. Veerapen, M. Tanaka, G.S. Besra, and J.G. Cyster (2011) Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone. J. Exp. Med. 208: 1941-1948.
Pellicci, D.G., A.J. Clarke, O. Patel, T. Mallevaey, T. Beddoe, J. Le Nours, A.P. Uldrich, J. McCluskey, G.S. Besra, S.A. Porcelli, L. Gapin, D.I. Godfrey, and J. Rossjohn (2011) Recognition of b-linked self glycolipids mediated by natural killer T cell antigen receptors. Nat. Immunol. 12: 827-833.
Garg, S., M. Sharma, C. Ung, A. Tuli, D.C. Barral, D.L. Hava, N. Veerapen, G.S. Besra, N. Hacochen, and M.B. Brenner (2011) Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. Immunity 35: 182-193.
Brennan, P.J., R.V. Tatituri, M. Brigl, E.Y. Kim, A. Tuli, J.P. Sanderson, S.D. Gadola, F.F. Hsu, G.S. Besra*, and M.B. Brenner (2011) Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat. Immunol. 12(12): 1202-1211. [*co-corresponding author]
Kalscheuer, R., K. Syson, U. Veeraraghaven, B. Weinrick, K.E. Biermann, Z. Liu, J.C. Sacchettini, G.S. Besra, S. Bornemann, and W.R. Jacobs, Jr. (2010) Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an a-glucan pathway. Nature Chemical Biology. 6: 376-384.
Birch, H.L., L.J. Alderwick, B.J. Appelmelk, J. Maaskant, A. Bhatt, A. Singh, J. Nigou, L. Eggeling, J. Geurtsen, and G.S. Besra (2010) A truncated lipoglycan from mycobacteria with altered immunological properties. Proc. Natl. Acad. Sci. USA. 107: 2634-2639.
Muindi, K., M. Cernadas, G.F.M. Watts, L. Royle, D.C.A. Neville, R.A. Dwek, G.S. Besra, P.M. Rudd, T.D. Butters, amd M.B. Brenner (2010) Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphinogolipids presented by mCD1d. Proc. Natl. Acad. Sci. USA. 107: 3052-3507.