Year of Graduation

2022

Level of Access

Restricted Access Thesis

Embargo Period

5-19-2022

Department or Program

Chemistry

First Advisor

Danielle Dube

Abstract

Helicobacter pylori is a gram-negative pathogenic bacteria that has been linked to the development of peptic ulcers and gastric cancers. Along with other pathogens, H. pylori has grown increasingly resistant to frontline antibiotics and has been named a priority pathogen by the World Health Organization. With the growing issue of antibiotic resistance, new targets to fight this bacterial pathogen are needed. H. pylori’s unique glycans are intriguing targets due to the exclusively bacterial monosaccharides they are composed of and their pivotal role in the cell’s ability to evade external threats including antibiotics. I hypothesized that perturbation of H. pylori’s glycan-coated membrane would “disarm” the bacteria and hypersensitize them to antibiotics. To test this hypothesis, glycan-altering agents were utilized to perturb three classes of glycans – lipopolysaccharides, peptidoglycans, and glycoproteins – on H. pylori. Bacteria bearing altered glycans induced by glycosylation inhibitors were scored for their sensitivity to the antibiotics levofloxacin and metronidazole using Epsilometer tests. Relative to untreated wild-type H. pylori, H. pylori bearing an altered glycocalyx exhibited heightened sensitivity to levofloxacin but not to metronidazole. These small molecule-induced results were recapitulated by comparing antibiotic sensitivity in wild-type H. pylori versus glycosylation mutants. Together, these data indicate that selectively altering different parts of H. pylori’s glycocalyx could be effective in hypersensitizing H. pylori to front-line antibiotics. In addition, a fluorescent monosaccharide analog was utilized to investigate the inner-workings of the H. pylori glycoprotein biosynthetic pathway. Preliminary findings indicated that the analog successfully inhibited glycoprotein biosynthesis and was altered while in the cell.

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