Existing antibiotics are becoming increasingly ineffective at eradicating infections, and have been shown to have long-term, deleterious effects on human health. Thus, there is an urgent need to develop novel therapeutics to facilitate the selective targeting of bacterial pathogens without disrupting the host microbiome. The distinctive glycans present on the surfaces of many bacterial pathogens provide a promising target for therapeutic intervention. Here we explored the use of a metabolic oligosaccharide engineering (MOE)-based therapeutic approach to selectively eradicate pathogenic bacteria without harming symbiotic species or host cells. In this two-step therapeutic approach, unnatural, azide-containing sugars are incorporated into surface glycoproteins of pathogens via endogenous pathways, then labeled cells are targeted for destruction using covalent antibiotics. Our studies suggest that derivatives of the common metabolic precursor, glucosamine, and the rare bacterial sugar, bacillosamine, are incorporated onto the surface of the gastric pathogen H. pylori, but are effectively absent from the surfaces of mammalian cells and the symbiotic species Bacteroides fragilis; thus, these sugars might serve as suitable targets for therapeutic intervention. Experiments are currently underway to assess the ability of a protoporphyrin IX photosensitizer based covalent therapeutic to selectively catalyze light-dependent killing of azide-covered H. pylori using these metabolic substrates. Ultimately, this work has the potential to introduce novel treatment options for people who are infected with H. pylori as well as other bacterial pathogens.

Glycan-based strategy for selectively targeting Helicobacter pylori

251st National Meeting (2016)

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