Assessing <i>O</i> -Naphthylmethyl and <i>O</i> -Anthracenemethyl Glycosides as Metabolic Inhibitors of Bacterial Glycan Biosynthesis

Bacterial glycans play a crucial role in survival and pathogenesis, making them attractive antibiotic targets. Unlike mammalian glycans, bacterial glycans incorporate rare sugars such as bacillosamine, <i>N</i>-acetylfucosamine, and 2,4-diacetamido-2,4,6-trideoxy galactose. To probe the role of bacterial glycans, we previously developed <i>O</i>-benzyl glycosides that metabolically inhibit <i>Helicobacter pylori</i> glycan biosynthesis and impair bacterial fitness. Here, we probed the efficacy of <i>O</i>-naphthylmethyl and <i>O</i>-anthracenemethyl glycosides, which bear larger aglycones relative to previously reported bacterial metabolic inhibitors. <i>O</i>-Naphthylmethyl d-<i>N</i>-acetylfucosamine inhibited <i>H. pylori</i> glycan biosynthesis, reduced biofilm formation, and impeded <i>H. pylori</i> growth at lower concentrations than its <i>O</i>-benzyl analog while leaving glycosylation of the commensal bacterium <i>Bacteroides fragilis</i> intact. By contrast, the <i>O</i>-anthracenemethyl glycosides tested were not effective metabolic glycan inhibitors. These metabolic inhibitors expand the bacterial glycoscience toolkit for probing protein glycosylation, help refine metabolic glycan inhibitor design parameters, and have the potential to set the stage for a glycan-based strategy to selectively target pathogens.