Helicobacter pylori (Hp) is a bacterial pathogen that infects over 50% of people worldwide, causing ulcers and gastric cancer in humans. Hp has evolved increasing resistance to the current antibiotic treatment. Therefore, there is a need for alternative antibiotic strategies to eradicate Hp. Here we explored a metabolic oligosaccharide engineering-based approach to target distinctive surface glycans present on Hp. We utilized a three-component process- 1) metabolic labeling of Hp’s glycans with azido-sugars, 2) reacting azide-labeled Hp glycans with bioorthogonal reactive partners conjugated to an immune stimulant, and 3) directing a host immune response against targeted Hp. In particular, we compared chemistries for the covalent delivery of the immune stimulant 2,4-dinitrophenyl (DNP) to azide-covered Hp. For our experiments, we compared our previously reported phosphine-DNP (Phos-DNP) conjugate to an analogous cyclooctyne-based conjugate. We synthesized two different cyclooctyne conjugates, based on dibenzoazacyclooctyne (DIBAC) and bicyclononyne (BCN), and then compared their reactivity and labeling selectivity with Phos-DNP. Our syntheses and biological results will be presented. Ultimately, this study has the potential to develop an optimally reactive covalent antibiotic that triggers selective killing of Hp.

Comparison of covalent delivery methods for immune-mediated targeting of Helicobacter pylori

251st National Meeting (2016)

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