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Deciphering Helicobacter pylori’s glycocode: uncovering & harnessing drug targets

Project Summary

Helicobacter pylori (Hp) is the leading cause of duodenal ulcers and gastritis worldwide. Unfortunately, existing antibiotics frequently fail to eradicate Hp infection and cure these ailments. The development of new treatments will be greatly aided by insights into the pathogenesis of Hp. Virulence of Hp appears to be directly linked to the pathogen’s ability to glycosylate proteins. Although Hp synthesizes a vast array of glycoproteins, what is not clear is the machinery responsible for their biosynthesis, how they can be harnessed to treat chronic Hp infection, and if they can be targeted selectively. The long-term goal of this project is to harness the power of chemistry to enable fundamental studies of bacterial glycosylation, particularly with respect to human disease. The objectives of this application are to identify Hp glycosylation machinery that could serve as drug targets, to develop a strategy to inactivate Hp based on its distinctive glycans, and to assess the selectivity of our targeting strategy for Hp over other bacteria. The central hypothesis of the application is that Hp’s glycoproteins are important for Hp’s fitness, can serve as targets for covalent delivery of therapeutics, and can be selectively targeted without broadly interfering with most other bacteria. Our hypothesis has been formulated on the basis of strong preliminary data produced in my laboratory, including the demonstration that Hp strains deficient in glycosylation machinery exhibit defects in glycoprotein synthesis. Further, my laboratory has reported that therapeutic probes can be covalently delivered to surface glycans on Hp. Finally, my lab has established that metabolic labeling of glycans is not uniform across bacterial species, thus setting the stage for selective targeting of glycans only found on pathogens. The rationale for the proposed research is that novel targets of therapeutic intervention will be revealed, resulting in new and innovative approaches to treat bacterial disease. The proposed research is innovative because it will lead to a targeted antibacterial strategy that has the potential to treat Hp infection while minimizing the effects on other bacteria, a substantive departure from the status quo. This contribution is an important step in a continuum of research that is expected to lead to novel anti-Hp therapies.

Relevance of Research

The proposed studies are relevant to public health because they have potential applicability to understanding the pathogenesis of Helicobacter pylori infection, as well as providing new targets for therapeutic interventions that will aid patients suffering from ulcers and gastritis. Thus, the proposed research is relevant to the part of the NIH’s mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human illness.