Research Theme within School of Biosciences: Molecular Microbiology
Lipid Metabolites of mycobacteria: pathways to biosynthesis and role in virulence
Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis remains the most successful human pathogen. Though considered to be under control only 20 years ago, a number of factors like the spread of HIV and the emergence of drug resistant MTB strains have led to the resurgence of this disease. There is thus a clear and urgent need to extend our understanding of the physiology and pathogenicity of MTB with the aim of developing new therapeutics and vaccines.
Complex lipids play an important role in the biology of the bacterium as a large proportion of the genome contains genes proposed to be involved in lipid biosynthesis. A distinct lipid rich outer envelope helps MTB counteract a number of inhospitable conditions in vivo, and many mycobacterial lipids display immunomodulatory activities when tested in models of infection. Mycobacterial lipids thus play an important role in virulence. Furthermore, some of these lipids have been shown to be essential for growth and the enzymes involved in the biosynthesis of these lipids represent potential drug targets. The pathways involved in lipid biosynthesis thus merit a detailed study.
A broad aim of my research is understand how mycobacterial lipids are made, and the impact they have on virulence. We use a genetic approach to address these questions by generating mutant strains that are defective in these pathways. Research in my laboratory is funded by a Career Development Award, and Research Grants from the Medical Research Council.
Sarkar D., Sidhu M., Singh A., Chen J., Lammas D.A., van der Saar A., Besra G.S. and Bhatt A. (2011) Identification of a glycosyltransferase from Mycobacterium marinum involved in addition of a caryophyllose moiety in lipooligosaccharides J Bacteriol 193:2336-2340.
Khan S., Nagarajan N.S., Parikh A., Samantaray S., Singh A., Kumar D., Roy R.P., Bhatt A. and Nandicoori V.K. (2010) Phosphorylation of enoyl-ACP reductase InhA impacts mycobacterial growth and survival. J Biol Chem 285:37860-37871.
Taylor R.C., Brown A.K., Singh A., Bhatt A. and Besra G.S. (2010) Characterization of a beta-hydroxybutyryl-CoA dehydrogenase from Mycobacterium tuberculosis. Microbiol 156: 1975-1982.
Birch H.L., Alderwick L.J., Appelmelk B.J., Maaskant J., Bhatt A., Singh A., Nigou J., Eggeling L., Geurtsen J. and Besra G.S. (2010) A truncated lipoglycan from mycobacteria
with altered immunological properties. Proc Natl Acad Sci 107: 2634-2639.
Chen J., Kriakov J., Singh A., Jacobs Jr. W.R., Besra G.S. and Bhatt A. (2009) Defects in glycopeptidolipid biosynthesis confer phage I3 resistance in Mycobacterium smegmatis
Microbiol 155: 4050-4057.
Brown A.K., Taylor R.C., Bhatt A., Fütterer K. and Besra G.S. (2009) Platensimycin activity against mycobacterial beta-ketoacyl-ACP synthases. PLoS ONE 17: e6306.
Bhatt A., Brown A.K., Singh A., Minnkin D.E. and Besra G.S. (2008) “Loss of a mycobacterial gene encoding a reductase leads to an altered cell wall containing beta-oxo-mycolic acid analogs and accumulation of ketones.” Chem Biol 15: 930-939.
Bhowruth V., Alderwick L.J., Brown A.K., Bhatt A. and Besra G.S. (2008) “Tuberculosis: a balanced diet of lipids and carbohydrates.” Biochem Soc Trans 36: 555”“565.
Dover L.G., Bhatt A., Bhowruth V., Willcox B.E. and Besra G.S. (2008) “New drugs and vaccines for drug-resistant Mycobacterium tuberculosis infections.” Expert Rev Vaccines 7: 481-497
Brown A.K., Bhatt A., Singh A., Saparia E., Evans A.F. and Besra G.S. (2007) “Identification of the dehydratase component of the mycobacterial mycolic acid synthesizing fatty acid synthase-II complex.” Microbiol 153: 4166-4173.
Brown A.K., Papaemmanouil A., Bhowruth V., Bhatt A., Dover L.G. and Besra G.S. (2007) “Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II.” Microbiol 153: 3314-3322.
Bhatt A., Molle V., Besra G.S., Jacobs Jr. W.R. and Kremer L. (2007) “The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid fastness, pathogenesis and in drug development.” Mol Microbiol 64: 1442-1454.
Bhatt A., Fujiwara N., Bhatt K., Gurcha S.S., Kremer L., Chen B., Chan J., Porcelli S., Kobayashi K., Besra G.S. and Jacobs Jr. W.R. (2007) “Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and subclinical latent tuberculosis in immuno-competent mice.” Proc. Natl. Acad. Sci. USA 104: 5157-5162.
Bhatt K., Gurcha S.S., Bhatt A., Besra G.S. and Jacobs Jr. W.R. (2007) “Two polyketide-synthase-associated acyltransferases are required for sulfolipid biosynthesis in Mycobacterium tuberculosis.” Microbiol. 153: 513-520.
Bhatt A., Kremer L., Dai A.Z., Sacchettini J.C. and Jacobs Jr. W.R. (2005) “Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis.” J. Bacteriol. 187: 7596-7606.
Matsunaga I., Bhatt A., Young D.C., Cheng T-Y., Besra G.S., Briken V., Porcelli S.A., Jacobs Jr. W.R. and Moody D.B. (2004) “Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T Cells.” J. Ex. Med. 200: 1559-1569