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Restricted Access Thesis

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First Advisor

Danielle Dube


Helicobacter pylori is a human pathogen and is the leading cause of gastric cancer. Current treatments have decreasing effectiveness due to increased antibiotic resistance. Further, damage to the commensal bacteria of the gut microbiome is common with broad spectrum antibiotics. Therefore, there is a need to develop antibiotics that are both specific to H. pylori and are effective. One set of potential targets are glycans. These species-specific sugar-containing biomolecules are found on the surface of most cells, including H. pylori. Glycoproteins are proteins covalently modified with sugars, and in H. pylori, when inhibited, appear to reduce fitness. Unfortunately, the structure and biosynthesis of glycoproteins remains poorly understood. Recent work has shown that there may be some overlap between H. pylori glycoprotein and lipopolysaccharide biosynthesis. It appears that the pathways share glycosyltransferases that create a precursor glycan. Then, some of these glycans are attached to lipid carriers to make lipopolysaccharide, and some are attached to proteins to make glycoproteins. To probe this model, two key genes potentially involved in the bifurcation were selected for knockout, wzk and waaL. Bioinformatics was also used to identify three candidate oligosaccharide transferases (OSTs), which could attach the glycan to the protein carrier. The glycoprotein and lipopolysaccharide profiles of strains with targeted mutations in these five genes were analyzed, allowing for a revision of the working model of glycoprotein biosynthesis to show that the bifurcation occurs at an earlier stage than originally believed, as well as potentially identifying HPG27_1179 as the OST.


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