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Restricted Access Thesis

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First Advisor

Danielle Dube


Novel antibiotics are urgently needed due to the increasing ineffectiveness of existing antibiotics and their deleterious impacts on the host microbiome. Bacterial glycans are intriguing targets for selective interference because of their distinctive structures that vary across species. Moreover, these molecules have functional significance and mediate motility, biofilm formation, and host immune evasion. Our laboratory recently demonstrated that metabolic inhibitors based on rare bacterial monosaccharide scaffolds interfere with glycoprotein elaboration in Helicobacter pylori and cause a corresponding reduction in biological fitness. This work primarily aims to explore the species-specificity of these inhibitors by investigating their effects in diverse bacterial species including the gut microbes Campylobacter jejuni and Bacteroides fragilis. The effect of a panel of metabolic inhibitors on glycan biosynthesis was investigated via Western Blot and flow cytometry. Inhibitors were also tested for their capacity to induce defects in biological fitness, including reductions in growth, motility, and biofilm production. Intriguingly, metabolic inhibitors displayed differential effects across these three bacterial species. For example, inhibitors that had significant effects on glycan production in H. pylori had no detectable effects on glycoprotein biosynthesis in C. jejuni. By contrast, two different compounds induced glycan biosynthesis defects in B. fragilis. Together, these results indicate that metabolic inhibitors based on bacterial monosaccharides have the potential to induce species-specific disruption of glycosylation. Preliminary studies also suggest these metabolic inhibitors may also re-sensitize antibiotic-resistant bacteria to antibiotics that are typically ineffective. In the end, this work sets the stage for selectively disrupting the viability of bacteria of interest.


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