Helicobacter pylori is a bacterial pathogen in the human digestive tract that has been associated with both stomach ulcers and stomach cancer. Currently, the recommended treatment of H. pylori infection is a “triple therapy” that is suboptimal for eradicating the bacteria due to antimicrobial resistance. Thus, there is an urgent need to identify new approaches to target H. pylori. H. pylori’s glycans offer potential targets, as these structures are expressed on H. pylori but absent from host cells. Moreover, H. pylori’s glycans are important for adhesion to host cells, biofilm formation, and motility, all features that enable colonization. We previously demonstrated that H. pylori incorporates azide-containing analogs of rare, exclusively bacterial monosaccharides into its surface glycoproteins. In this work, two classes of substrate-based analog inhibitors, including chain terminators and substrate decoys, were designed based on these scaffolds and explored for their ability to interfere with H. pylori’s glycan biosynthesis. To test the ability of the inhibitors to elicit glycosylation defects in H. pylori, glycoprotein biosynthesis in strains treated with and without the inhibitors was analyzed. Initial results suggest that several of the proposed inhibitors interfere with glycan biosynthesis. Experiments are underway in our laboratory to further characterize the glycan truncation products produced by these inhibitors and their effects on H. pylori’s fitness. Ultimately, the targeting of bacterial pathogens through their unique glycans has the potential to provide clinicians with new and resourceful antibiotics.

Interfering with the biosynthesis of Helicobacter pylori’s glycans

2019 Spring National Meeting

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