Bacterial glycoproteins are frequently linked to pathogenesis and contain distinctive glycans that are absent from humans. We set out to develop an antibiotic strategy based on rare glycans present on the pathogenic bacteria Helicobacter pylori (Hp). In this study, metabolic labeling of bacterial glycans with azide-containing sugars allowed selective delivery of covalent therapeutics to azide-covered Hp. We established that Hp's surface glycans are labeled by treatment with the metabolic substrate peracetylated N-azidoacetylglucosamine (GlcNAz); in contrast, eukaryotic cell surfaces are devoid of azides upon treatment with GlcNAz. We further developed a series of immune stimulant-based and photosensitizer-based therapeutics that can be covalently delivered to azide-covered Hp. Finally, we assessed the ability of these covalent therapeutics to induce killing of azide-labeled Hp. These studies set the stage for further development of this glycosylation-based therapeutic strategy to eradicate Hp infection. Broadly, this work introduces a new paradigm for the development of antibiotics that target bacteria based on their unique glycans.

Glycans in pathogenic bacteria � potential for targeted covalent therapeutics

248th National Meeting (2014)

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