Synthetic UDP-Furanoses as Potent Inhibitors of Mycobacterial Galactan Biogenesis

SummaryUDP-galactofuranose (UDP-Galf) is a substrate for two types of enzymes, UDP-galactopyranose mutase and galactofuranosyltransferases, which are present in many pathogenic organisms but absent from mammals. In particular, these enzymes are involved in the biosynthesis of cell wall galactan, a polymer essential for the survival of the causative agent of tuberculosis, Mycobacterium tuberculosis. We describe here the synthesis of derivatives of UDP-Galf modified at C-5 and C-6 using a chemoenzymatic route. In cell-free assays, these compounds prevented the formation of mycobacterial galactan, via the production of short “dead-end” intermediates resulting from their incorporation into the growing oligosaccharide chain. Modified UDP-furanoses thus constitute novel probes for the study of the two classes of enzymes involved in mycobacterial galactan assembly, and studies with these compounds may ultimately facilitate the future development of new therapeutic agents against tuberculosis.

► Novel UDP-furanoses, modified at C-5 or C-6, were chemoenzymatically prepared
► UDP-furanose derivatives inhibit galactan assembly at concentrations as low as 9 μM
► Inhibition of galactan synthesis is due to the formation of “dead-end” intermediates
► These UDP-furanoses are new tools for probing mycobacterial cell wall assembly