Inhibitors of Mycobacterial Cell Wall Biosyntheis
A major research effort in the group has been the identification of inhibitors of glycosyltransferases responsible for cell wall polysaccharide biosynthesis in Mycobacterium tuberculosis, the organism that causes tuberculosis. As part of these investigations, we have recently expressed a galactosyltransferase (glfT), that is critical for mycobacterial viability. Thus, compounds that inhibit this enzyme are potential anti-TB drugs. We are now mapping the substrate specificity of glfT, and have developed a high throughput assay for the screening of potential inhibitors. In parallel with these investigations, inhibitors are being synthesized and we will probe the three dimensional structure of the protein using X-ray crystallography and NMR methods. We are also extending our work to a mannosyltransferase (ManT) involved in the biosynthesis of the mycobacterial cell wall.
Rhamnolipids as Anti-infectives and Remediation Agents
A new project in the group is the synthesis of analogs of rhamnolipids (below), which are a group of structurally interesting glycolipids produced by Pseuudomonas aeruginosa. These compounds are believed to the virulence factors and also possess anti-bacterial properties. They have also been suggested to have potential in the remediation of soil contaminated with pollutants. However, structure-function studies of these molecules are non-existent. We are synthesizing analogs of these compounds to understand the molecular features that lead to their biological activity or their effectiveness in the remediation of waste sites.
Synthesis of Glycoconjugates Containing Furanose Rings
We have a long-standing interest in the synthesis of oligosaccharides containing monosaccharides in the five-membered ring (furanose) form. These species are constituents of a number of key glycoconjugates from bacteria, fungi, and parasites. In addition to the total synthesis of targets, we also develop new methodologies as needed, often with the help of mechanistic investigations. Among the targets currently of interest are large fragments of mycobacterial arabinogalactan (1, the synthesis of which we recently completed), and structurally-interesting oligosaccharides found in bacteria (e.g., 2 and 3).
Conformational Analysis of Molecules Containing Five-Membered Rings
In conjunction with our studies on the synthesis of compounds containing furanose and other five-membered rings, we are studying the conformation of these molecules. These investigations are motivated by the belief that an understanding of the conformation of these molecules will facilitate the identification of inhibitors of enzymes involved in furanoside biosynthesis. Our studies in this area involve a combination NMR spectroscopy, and computational chemistry (including molecular mechanics, ab initio, and density functional theory calculations) together with chemical synthesis. Among the projects in this area are a study of the effect of the lipid length and branching pattern on the ring conformation of glycolipids such as 4 and conformational analysis of galactofuranose-containing oligosaccharides (e.g., 5).