Design, Synthesis, and Biological Evaluation of Lipid‐Modified Derivatives of Tunicamycins

Naturally occurring antibiotic tunicamycin targets bacterial peptidoglycan biosynthesis by inhibiting bacterial phospho-N-acetylmuraminic acid (MurNAc)-pentapeptide translocase (MraY), but it also inhibits human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT), leading to cytotoxicity. This study thoroughly investigated the structure-activity relationship of the fatty acyl side chain of tunicamycin to develop MraY-selective inhibitors, based on structural differences between MraY and GPT. Longer alkyl chains and flexible structures were found to favor MraY inhibitory activity, and benzene rings were acceptable for binding. The hybrid analogue containing oleoyl group, which contributed most significantly to MraY inhibitory activity, and the MurNAc moiety, which is important for MraY-selective inhibition, showed enhanced MraY inhibitory activity as well as improved antibacterial activity against S. aureus and E. faecium.