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 which of these species are involved in host-pathogen interactions, 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 glycoproteins 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 involved in host-pathogen interactions, can serve as targets for covalent delivery of therapeutics, and can be selectively targeted without broadly interfering with most bacteria. Our hypothesis has been formulated on the basis of strong preliminary data produced in my laboratory, including the demonstration that a subset of Hp's surface glycoproteins are overexpressed in the presence of host cells. Further, my laboratory has reported that therapeutic probes can be covalently delivered to surface glycans on Hp. Finally, my lab has demonstrated 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 bac- terial disease. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify Hp glycoproteins involved in host-pathogen interactions; 2) Develop therapeutics that target Hp's surface glycans; and 3) Assess the selectivity of our targeting strategy for Hp. Under the first aim, the importance of Hp's glycoproteins in binding to host cells will be evaluated, and an already proven approach will be used to identify Hp glycoproteins that are preferentially overexpressed in the presence of host cells. Under the second aim, metabolically labeled glycans on Hp's surface will be targeted with therapeutics, and then the damage to Hp will be measured. Under the third aim, the incorporation of azidosugars onto surfaces of pathogenic and symbiotic bacteria will be evaluated, and the selectivity of targeting Hp with covalent therapeutics will be analyzed. 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 significant because it is an important step in a continuum of research that is expected to lead to development of glycosylation-based strategies to treat ulcers and gastritis.
The proposed studies are relevant to public health because they are in an important and under- investigated area of bacterial biology that has 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 an gastritis. Thus, the proposed research is relevant to the part of the NIH's mission that pertains t developing fundamental knowledge that will potentially help to reduce the burdens of human illness.
| Clark, Emily L; Emmadi, Madhu; Krupp, Katharine L et al. (2016) Development of Rare Bacterial Monosaccharide Analogs for Metabolic Glycan Labeling in Pathogenic Bacteria. ACS Chem Biol 11:3365-3373 |
