Bacterial cells present a wide diversity of saccharides that decorate the cell surface and help mediate interactions with the environment. Among those saccharides, l-rhamnose was abundantly found in bacterial cell wall but not in mammalian cells, and so provides a unique approach to investigate the bacterial glycan code and a promising target for antibiotic development. The biosynthesis of l-rhamnose is well characterized but the molecular mechanism of rhamnosyltransfer is less understood. In this study, we obtained a series of dTDP-β-l-rhamnose analogs via chemical synthesis and chemoenzymatic approach as probes to investigate the substrate tolerance by corresponding bacterial l-rhamnosyltransferase. The chemical synthesis and characterization of dTDP-β-l-rhamnose also help to clarify the controversial anomeric figure of this compound. By introducing substituents at 6-position of l-rhamnose moiety and alternation of the stereochemistry of OH groups at 2 and 4 positions, we found that these analogs showed moderate binding affinity to the glycosyltransferase compared to the natural substrate dTDP-l-Rha, which will inform the development of other tools to further study the bacterial glycan code.

Synthesis of dTDP-l-rhamnose analogues to explore the substrate tolerance of bacterial glycosyltransferase

ACS Spring 2022

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