Research Interest:

Mycobacteria are endowed with a diverse range of lipid-based glycoconjugates. Specific carbohydrate epitopes on these glycoconjugates constitute the immunogenic determinants implicated in immunopathogenesis of mycobacterial diseases. The mycobacterial cell wall has been attractive drug targets for many anti-mycobacterial drugs in use and in development. Research interests in mycobacterial infections, as manifested in tuberculosis is focused on the effect of ethambutol, a drug known to inhibit arabinan (a key macromolecular entity) biosynthesis, and examine the resultant changes in the cell wall structures as a consequence of drug treatment or induced drug resistance.

Our work covers a number of areas concerned with mycobacterial glycan biosynthesis. We approach these problems through biochemical, biophysical, genetic and chemical methods.

Current projects are:

[1] Identify genes encoding the biosynthesis of these structures so that their roles in pathogenesis can be evaluated and to provide tools for rational drug design for new antimycobacterial drugs.

[2] Elucidate structure-function relationships of the multi-subunit, membrane-bound enzyme complexes responsible for the steps in the assembly of biologically active carbohydrate based glycoconjugates.

[3] In Drug Discovery- medium-throughput screening and medicinal chemistry (in collaboration with Mike McNeil and Richard Lee) involving the chemical synthesis of inhibitors as drug leads.

[4] Complete structure determination of cell wall glycoconjugates relying on a comprehensive scheme of physico-chemical methods including chemical derivatization, chromatographic fractionation, sequential exo-glycosidase digestions, mass spectrometry (MS) and two dimensional nuclear magnetic resonance (NMR).

For a variety of biological samples, magic angle spinning is efficient at averaging left-over components of the solid state line width, and leads to NMR spectra that display resolution approaching that of liquid samples. Such methods have been termed High Resolution MAS (HR-MAS) High Resolution Magic Angle Spinning Spectroscopy.

HR-MAS one- and two- dimensional nuclear magnetic spectroscopy (NMR) has been used to study in vivo biological samples such as tissues and cells. We are interested in developing this technique to analyze liver, spleen and lung tissues infected with M. leprae and M. tuberculosis to observe metabolic alterations before they are morphologically detectable, and to correlate then to hisopathological features and diagnosis.