Helicobacter pylori is a ubiquitous pathogen associated with duodenal ulcers and stomach cancer. The current treatment of the disease is “triple therapy” but negative side effects and increasing antibiotic resistance have resulted in a pressing need for new, more selective therapies. The glycans that coat the surface of H. pylori are compelling therapeutic targets because they contain unusual 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 the bacteria’s ability to infect the host. We previously demonstrated O-glycoside inhibitors based on rare bacterial monosaccharides effectively interrupted glycan biosynthesis. A recent publication by Wang et al. showed a novel class of metabolic inhibitors, S-glycosides, were effective at &gt; 10-fold lower concentrations than O-glycosides in mammalian systems. We assessed S-glycosides based on rare bacterial monosaccharides for their ability to truncate glycan biosynthesis in H. pylori, as well as their downstream effects on bacterial fitness. The S-glycoside inhibitors effectively impeded glycan biosynthesis and affected bacterial fitness in a compound-dependent manner. We plan to test these compounds on other pathogenic and symbiotic bacterial species to investigate whether they elicit species-specific defects. Ultimately, selectively targeting bacterial pathogens through their unique glycans has the potential to expand our antibiotic arsenal.

Thioglycosides act as metabolic inhibitors of bacterial glycosylation

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