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Increasing antibiotic resistance has resulted in a pressing need for new, selective therapies. Helicobacter pylori is a prime example of a multi-drug resistant pathogen, which has infected about 50% of the global population. The glycans that coat the surface of bacteria are compelling therapeutic targets because they contain distinct monosaccharides that are absent from human cells and are linked to pathogenesis. As such, disrupting the synthesis of fully functional glycans presents a possible pathway of inhibiting a bacteria’s ability to infect the host. The Dube lab previously demonstrated O-glycoside inhibitors based on rare bacterial monosaccharides were effective in disrupting glycan biosynthesis in H. pylori. A recent study by Wang et al. established in mammalian systems that a novel class of metabolic inhibitors, thioglycosides (S-glycosides), were effective at >10-fold lower concentrations than O-glycosides due to their increased stability in cells. This project assessed a panel of three S-glycosides based on rare bacterial monosaccharides for their ability to truncate glycan biosynthesis and elicit fitness defects via western blot analysis and fitness assays, respectively. These compounds were screened in the pathogenic bacteria H. pylori, the commensal gut organism B. fragilis, and mammalian cells. S-glycosides altered glycan biosynthesis and affected bacterial fitness in H. pylori but not in B. fragilis. The inhibitors did not impact mammalian cell glycosylation or growth, suggesting selectivity of inhibitors for pathogenic bacteria. Results demonstrate S-glycosides are effective at comparable concentrations to O-glycosides. Selectively targeting bacterial pathogens through their unique glycans has the potential to expand our antibiotic arsenal.
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