This Fogarty International Research Collaboration Award (FIRCA) is directed toward understanding cell wall biosynthesis in Mycobacterium tuberculosis. The FIRCA supports Specific Aim 1 to define the pathway by which M. tuberculosis converts 5-phosphoribosyl pyrophosphate (pRpp) into the donor decaprenylphosphate-D-arabinose (DPA). Thus far efforts to isolate the postulated intermediates 5-phosphoarbinosyl pyrophosphate (pApp) and decaprenylphosphate-5-phospho-D-arabinose (5P-DPA) have been unsuccessful, presumably because these intermediates are immediately transformed to subsequent compounds in the synthetic pathway. A collaborator will prepared the suspected intermediates pApp and 5P-DPA and the PI will then determine if they can be converted to DPA. Once these or other compounds have been shown to be intermediates, the research will be extended to make potential inhibitors of the formation of DPA. These potential inhibitors will be analogs of pApp and 5P-DPA and will be prepared using a combinatorial approach. This approach will start with peptide glycosides of arabinose-5-phosphate and hits will then be further refined in a medicinal chemical approach.
