Overuse of antibiotics has fueled the rise of antibiotic-resistant pathogenic bacteria and alterations in the gut microbiome of treated individuals. Thus, there is an urgent need for alternative approaches to target bacterial pathogens. Immunotherapies that target bacterial pathogens based on their distinctive glycan coat offers a potential alternative. Previous work in our laboratory described a metabolic oligosaccharide engineering-based approach to first label cellular glycans with azide-containing sugars and then covalently deliver immune stimulants to azide-coated cells via bioorthogonal chemistry. Using this platform, azide-coated bacterial cells were targeted with a phosphine-based 2,4-dinitrophenyl (DNP) conjugate to trigger immune-mediated killing of Helicobacter pylori, albeit at relatively modest levels. In the present work, we sought to compare DNP-conjugates bearing three different azide-reactive components, a phosphine, a cyclooctyne, or an alkyne, that undergo Staudinger ligation, strain promoted azide-alkyne cycloaddition (SPAAC), and copper catalyzed azide-alkyne cycloaddition (CuAAC), respectively. Moreover, we explored the utility of this strategy for targeting an array of bacterial species including Helicobacter pylori, Campylobacter jejuni, and Bacterioides fragilis. Bacteria metabolically labeled with azidosugar and then treated with the cyclooctyne probe exhibited heightened susceptibility to immune cells relative to azide-free samples. By contrast, bacteria treated with the phosphine-based probe exhibited low levels of cell death, whereas even azide-free bacteria treated with the alkyne suffered from off-target toxicity. These results suggest that SPAAC has the potential to form the basis of immune-mediated strategies to target select bacterial populations based on their glycan coat.

Using metabolic oligosaccharide engineering to induce immune-mediated cell killing of diverse bacterial pathogens

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.