Research interests

 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. 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.

Personal Web Site 

Publications

Chosen Articles:

1.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. 

2. 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.

3.Chen J., J. Kriakov, A. Singh, W.R. Jacobs, G.S. Besra, and A. Bhatt (2009) Defects in glycopeptidolipid biosynthesis confer phage I3 resistance in Mycobacterium smegmatis. Microbiology 155: 4050-4057.

4.Brown, A.K., R.C. Taylor, A. Bhatt, K. Futterer, and G.S. Besra (2009) Plattensimycin activity against mycobacterial b-ketoacyl-ACP synthases. PLoS ONE 4: e6306.

5.Veyron-Churlet, V. Molle, R.C. Taylor, A.K. Brown, G.S. Besra, I. Zanella-Cleon, K. Futterer, and L. Kremer (2009) The Mycobacterium tuberculosis b-ketoacyl-ACP synthase III (mtFabH) activity is inhibited by phosphorylation on a single threonine residue. J. Biol. Chem. 284: 6412-6424.

6.Al-Balas, Q., N.G. Anthony, B. Al-Jaidi, A. Alnimr, G. Abbott, A.K. Brown, R.C. Taylor, G.S. Besra, T.D. McHugh, S.H. Gillespie, B.F. Johnston, S.P. Mackay, and G.D. Coxon (2009) Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium  tuberculosis H37Rv and the b-ketoacyl-ACP synthase mt-FabH. PLoS ONE 4:e5617.

7.Mishra, A.K., S. Batt, K. Krumbach, L. Eggeling and G.S. Besra (2009) Characterisation of the Corynebacterium glutamicumDpimB’DmgtA double deletion mutant and the role of Mycobacterium tuberculosis orthologues Rv2188c and Rv0557 in glycolipid biosynthesis. J. Bacteriol. 191: 4465-4472.

8.Torrelles, J.B., L.E. Desjardin, J. MacNeil, T.M. Kaufman, B. Kutzbach, R. Knaup, T.R. McCarthy, S.S. Gurcha, G.S. Besra, S. Clegg, and L.S. Schlesinger (2009) Inactivation of Mycobacterium tuberculosis mannosyltransferase pimB reduces cell wall lipoarabinommannan and lipomannan content and increases the rate of bacterial-induced human macrophage cell death. Glycobiology 19: 743-755.

9.Usha, V., L.G. Dover, D.I. Roper, K. Futterer, and G.S. Besra (2009) Structure of the diaminopimelate epimerase DapF from Mycobacterium tuberculosis. Acta Crystallogr. D Biol. Crystallogr. 65: 383-387.

10. Borg, N.A., K.S. Wun, L. Kjer-Nielsen, M.C. Wilce, D.G. Pellicci, R. Koh, G.S. Besra, M. Bharadwaj, D.I. Godfrey, J. McCluskey, and J. Rossjohn (2007) CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448: 44-49.

11. Wang, F., R. Langley, G. Gulten, L.G. Dover, G.S. Besra, W.R. Jacobs Jr., and J.C. Sacchettini (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J. Exp. Med. 204: 73-78.

12. Bhatt, A., N. Fujiwara, K. Bhatt, S.S. Gurcha, L. Kremer, B. Chen, J. Chan, S.A. Porcelli, K. Kobayashi, G.S. Besra, and W.R. Jacobs, Jr. (2007) Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and sub-clinical latent tuberculosis in immunocompetent mice. Proc. Natl. Acad. Sci. USA 104: 5157-5162.

13. Elzen, P. van den, S. Garg, L. Leon, M. Brigl, E. Leadbetter, J. Gumperz, C.C. Dascher, T-Y Cheng, F. Sacks, P. Illarionov, G.S. Besra, S.C. Kent, D.B. Moody, and M.B. Brenner (2005) An apolipoprotein mediated pathway of exogenous lipid antigen presentation. Nature 437: 906-910.

14. Koch, M., V.S. Stronge, D. Shepherd, S.D. Gadola, B. Mathew, G. Ritter, A.R. Fersht, G.S. Besra, R.R. Schmidt, E.Y. Jones, and V. Cerundolo (2005) The crystal structure of human CD1d with and without alpha-galactosylceramide. Nature Immunology 6: 819-826

15. Moody, D.B., V. Briken, T.Y. Cheng, C. Roura-Mir, M.R. Guy, D.H. Geho, M.L. Tykocinski, G.S. Besra, and S.A. Porcelli (2002) Lipid length controls antigen entry into endosomal and non-endosomal pathways for CD1b presentation. Nature Immunology 3(5): 435-442.

16. Moody, D.B., W. Muhlecker, T. Ulrichs, D. Young, E. Grant, J.P. Rosat, M.R. Brenner, V. Reinhold, C. Costello, G.S. Besra, and S.A. Porcelli (2000) CD1c-mediated immune responses in Mycobacterium tuberculosis. Nature 404(6780): 884-888.

17. Ronning, D.R., T. Klabunde, G.S. Besra, V.D. Vissa, J.T. Belisle, and J.C. Sacchettini (2000) Crystal structure of the secreted form of Antigen 85C reveals potential targets for mycobacterial drugs and vaccines. Nature Structural Biology 7(2): 141-146.

18. Belisle, J.T., V.D. Vissa, T. Sievert, K. Takayama, P.J. Brennan, and G.S. Besra (1997) Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276: 1420-1422.

19. Moody, D.B., B.B. Reinhold, M.R. Guy, E.M. Beckman, D.E. Frederique, S.T. Furlong, S. Ye, V.N. Reinhold, P.A. Seiling, R.L. Modlin, G.S. Besra, and S.A. Porcelli (1997) Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278: 283-286.

B. Remaining Publications 2010-1996:

Barral, P., P. Polzella, A. Bruckbauer, N. van Rooijen, G.S. Besra, V. Cerundolo, and F.D. Batista (2010) CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nature Immunology 11: 303-312.

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.

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.

Leadbetter, E.A., M. Brigl, P. Illarionov, N. Cohen, M.C. Luteran, S. Pillai, G.S. Besra, and M.B. Brenner (2008) NK T cells provide lipid antigen-specific cognate help for B cells. Proc. Natl. Acad. Sci. (USA). 105: 8345-8350.

Veerapen, N., E.A. Leadbetter, M.B. Brenner, L.R. Cox, and G.S. Besra (2010) Synthesis of a novel a-galactosyl ceramide haptenated-lipid antigen, a useful tool in demonstrating the involvement of iNKT cells in the production of antilipid antibodies. Bioconjug. Chem. 21: 741-747.

Odyniec, A.N., D.C. Barral, S. Garg, R.V. Tatituri, G.S. Besra, and M.B. Brenner (2010) Regulation of Cd1 antigen presenting complex stability. J. Biol. Chem. 285: 11937-11947.

Fox, L.M., D.G. Cox, J.L. Lockridge, X. Wang, X. Chen, L. Scharf, D.L. Trott, R.M. Ndonye, N. Veerapen, G.S. Besra, A.R. Howell, M.E. Cook, E.J. Adams, W.H. Hildebrand, and J.E. Gumperz (2009) Recognition of lyso-phospholipids by human natural killer T lymphocytes. PLoS Biology 7:e100028.

Im, J.S., P. Arora, G. Bricard, A. Molano, M.M. Venkataswamy, I. Baine, E.S. Jerud, M.F. Goldberg, A. Baena, K.O. Yu, R.M. Ndonye, A.R. Howell, W. Yuan, P. Cresswell, Y.T. Chang, P.A. Illarionov, G.S. Besra, and S.A. Porcelli (2009) Kinetics and cellular site of glycolipid loading control the outcome of natural killer T cell activation. Immunity 30: 888-898.

Birch, H.L., L.J. Alderwick, D. Rittmann, K. Krumbach, H. Etterich, A. Grzegorzewicz, M.R. McNeil, L. Eggeling, and G.S. Besra (2009) Identification of a t-rhamnopyranosyltransferase (RptA) involved in Corynebacterium glutamicum cell wall biosynthesis. J. Bacteriol. 191: 4879-4887.

Al-Balas, Q., N.G. Anthony, B. Al-Jaidi, A. Alnimr, G. Abbott, A.K. Brown, R.C. Taylor, G.S. Besra, T.D. McHugh, S.H. Gillespie, B.F. Johnston, S.P. Mackay, and G.D. Coxon (2009) Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium tuberculosis H37Rv and the b-ketoacyl-ACP synthase mt-FabH. PLoS ONE 4:e5617.

Mishra, A.K., S. Batt, K. Krumbach, L. Eggeling and G.S. Besra (2009) Characterisation of the Corynebacterium glutamicumDpimB’DmgtA double deletion mutant and the role of Mycobacterium tuberculosis orthologues Rv2188c and Rv0557 in glycolipid biosynthesis. J. Bacteriol. 191: 4465-4472.

Kuns, R.D., E.S. Morris, K.P. MacDonald, K.A. Markey, H.M. Morris, N.C. Raffelt, T. Banovic, A.L. Don, V. Rowe, A.C. Burman, A.D. Clouston, C. Farah, G.S. Besra, P.A. Illarionov, M.J. Smyth, S.A. Porcelli, and G.R. Hill (2009) Invariant NKT-NK cell interactions dictate transplant outcome following a-galactosyl ceramide administration. Blood 113: 5999-6010.

Torrelles, J.B., L.E. Desjardin, J. MacNeil, T.M. Kaufman, B. Kutzbach, R. Knaup, T.R. McCarthy, S.S. Gurcha, G.S. Besra, S. Clegg, and L.S. Schlesinger (2009) Inactivation of Mycobacterium tuberculosis mannosyltransferase pimB reduces cell wall lipoarabinommannan and lipomannan content and increases the rate of bacterial-induced human macrophage cell death. Glycobiology 19: 743-755.

Usha, V., L.G. Dover, D.I. Roper, K. Futterer, and G.S. Besra (2009) Structure of the diaminopimelate epimerase DapF from Mycobacterium tuberculosis. Acta Crystallogr. D Biol. Crystallogr. 65: 383-387.

Garcia-Diaz, Y.R., J. Wojno, L.R. Cox, and G.S. Besra (2009) Synthesis of threitol ceramide and [14C]threitol ceramide, non-glycosidic analogues of the potent CD1d antigen a-galactosyl ceramide. Tetrahedron Asymm. 20: 747-753.

Bhowruth, V., D.E. Minnikin, E.M. Agger, P. Andersen, V.W. Bramwell, Y. Perrie, and G.S. Besra (2009) Adjuvant properties of a simplified C32 monomycolyl glycerol analogue. Bioorg. Med. Chem. Lett. 19: 2029-2032.

Guillonneau, C., J.D. Mintern, F.X. Hubert, A.C. Hurt, G.S. Besra, S.A. Porcelli, I.G. Barr, P.C. Doherty, D.I. Godfrey, and S.J. Turner (2009) Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity. Proc. Natl. Acad. Sci USA 106: 3330-3335.

Wehmeier, S., A.S. Varghese, S.S. Gurcha, B. Tissot, M. Panico, P.Hitchen, H.R. Morris, G.S. Besra, A. Dell, and M.C. Smith (2009) Glycosylation of the phosphate binding proteib PstS in Streptomyces coelicolor by a pathway that resembles protein O-mannosylation in eukaryotes. Mol. Microbiol. 71: 421-433.

Veyron-Churlet, V. Molle, R.C. Taylor, A.K. Brown, G.S. Besra, I. Zanella-Cleon, K. Futterer, and L. Kremer (2009) The Mycobacterium tuberculosis b-ketoacyl-ACP synthase III (mtFabH) activity is inhibited by phosphorylation on a single threonine residue. J. Biol. Chem. 284: 6412-6424.

Dao, D.N., K. Sweeney, T. Hsu, S.S. Gurcha, I.P. Nascimento, D. Roshevsky, G.S. Besra, J. Chan, S.A. Porcelli, and Jacobs, W.R. (2008) Mycolic acid modification by the mmaA4 gene of M. tuberculosis modulates IL-12 production. PLoS Pathog. 4(6): e1000081.

 Mishra, A.K., L.J. Alderwick, D. Rittmann, C. Wang, A. Bhatt, W.R. Jacobs, Jr., K. Takayama, L. Eggeling, and G.S. Besra (2008) Identification of a novel alpha(1-6)mannopyranosyltransferase (MptB) Corynebacterium glutamicum by deletion of a conserved gene, NCgl1505 affords a lipomannan and lipoarabinomannan deficient mutant. Mol. Microbiol. 68: 1595-1613.

Bhowruth, V., A.K. Brown, and G.S. Besra (2008) Synthesis and biological evaluation of NAS-21 and NAS-91 analogues as potential inhibitors of the FAS-II dehydratase enzyme of Mycobacterium tuberculosis. Microbiology. 154: 1866-1875

Garton, N.J., S.J. Waddell, A.L. Sherratt, S-M. Lee, R.J. Smith, C. Senner, J. Hinds, K. Rajakumar, R.A. Adegbola, G.S. Besra, P.D. Butcher, and M.R. Barer (2008) Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PloS Medicine. 5: e75.

Alahari, A., X. Trivelli, Y. Guerardel, L.G. Dover, G.S. Besra, J.S. Sacchettini, R.C. Reynolds, G.D. Coxon, and L. Kremer (2007) Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria. PloS One 12: e1343.

Brown, A.K., A. Bhatt, A. Singh, E. Saparia, A.F. Evans, and G.S. Besra (2007) Identification of the dehydratase component of the mycobacterial mycolic acid-synthesising fatty acid synthase-II complex. Microbiology, 153: 4166-4173.

Brown, A.K., A. Papaemmanouil, V. Bhowruth, A. Bhatt, L.G. Dover and G.S. Besra (2007) Flavonoid inhibitors as novel anti-mycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase-II. Microbiology 153: 3314-3322.

Bhowruth, V., A.K. Brown, S.J. Senior, J.S. Snaith, and G.S. Besra (2007) Synthesis and biological evaluation of a C-5 biphenyl thiolactomycin library. Bioorg. Med. Chem. Lett., 17: 5643-5646.

Mishra, A.K., L.J. Alderwick, D. Rittmann, R.V. Tatituri, J. Nigou, M. Gilleron, L. Eggeling, and G.S. Besra (2007) Identification of an alpha(1-6)mannopyranosyltransferase (MptA), involved in Corynebacterium glutamicum lipomannan biosynthesis, and identification of its orthologue in Mycobacterium tuberculosis. Mol. Microbiol. 65: 1503-1517.

Tatituri, R.V., P.A. Illarionov, L.G. Dover, J. Nigou, M. Gilleron, P.G. Hitchen, K. Krumbach, H.R. Morris, N. Spencer, A. Dell, L. Eggeling, and G.S. Besra (2007) Inactivation of Corynebacterium glutamicum NCgl0452 and the role of MgtA in the biosynthesis of a novel mannosylated glycolipid involved in lipomannan biosynthesis. J. Biol. Chem. 282: 4561-4572.

Seidel, M., L.J. Alderwick, H.L. Birch, H. Sahm, L. Eggeling, and G.S. Besra (2007) Identification of a novel arabinofuranosyltransferase AftB involved in a terminal step of cell wall arabinan biosynthesis in Corynebacteriabeae, such as Corynebacterium glutamicum and Mycobacterium tuberculosis. J. Biol. Chem. 282: 14729-14740.

Tatituri, R.V.V., L.J. Alderwick, A.K. Mishra, J. Nigou, M. Gilleron, K. Krumbach, P. Hitchen, A. Giordano, H.R. Morris, A. Dell, L. Eggeling and G.S. Besra (2007) Identification and structural characterization of a partially arabinosylated lipoarabinomannan variant isolated from a Corynebacterium glutamicum ubiA-mutant. Microbiology. 153: 2621-2629.

Sridharan, S., L. Wang, A.K. Brown, L.G. Dover, L. Kremer, G.S. Besra, and J.C. Sacchettini (2007) X-ray crystal structure of Mycobacterium tuberculosis ?-ketoacyl acyl carrier protein synthase II (mtKasB). J. Mol. Biol. 366: 469-480.

Molle, V., A.K. Brown, G.S. Besra, A.J. Cozzone, and L. Kremer (2006) The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J. Biol. Chem. 281: 30094-30193.

Alderwick, L.J., L.G. Dover, M. Seidel, R. Gande, H. Sahm, L. Eggeling, and G.S. Besra (2006) Arabinan deficient mutants of Corynebacterium glutamicum and consequent flux in decaprenylmonophosphoryl-D-arabinose metabolism. Glycobiology 16: 1043-1081.

Alderwick, L.J., V. Molle, L. Kremer, A.J. Cozzone, T.R. Dafforn, G.S. Besra, and K. Futterer (2006) Molecular structure of EmbR, a response element of Ser/Thr kinase signalling in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. (USA). 103: 2558-2563.

Alderwick, L.J., M. Seidel, H. Sahm, G.S. Besra, and L. Eggeling (2006) Identification of a novel arabinofuranosyl transferase (aftA) involved in cell wall arabinan biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 281: 15653-15661.