Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

4-10-2018

Graduate Advisor

Alexei V. Demchenko

Committee

Alexei V. Demchenko

Eike B. Bauer

Bruce C. Hamper

Stephen A. Kolodziej

Abstract

The Gram positive, cluster forming bacteria Staphylococcus aureus belongs to the family of opportunistic pathogens that may cause blood stream infections when the integrity of skin is broken and the immune system can no longer fight the infection. S. aureus has become one of the most frequent causes of infections in newborns, surgical patients, trauma and burn patients, patients receiving an implant, and dialysis patients with high mortality rates. As a matter of fact, S. aureus has become one of the largest public health and economic impacts amongst all bacterial infectious diseases worldwide. This situation is further complicated by the rapid increase in anti-microbial drug resistance. Since the S. aureus bacterial cell is surrounded by a polysaccharide capsule, preventive vaccination based on polysaccharide or saccharide-protein conjugates is a suitable tool against the bacterial invasion. Serotyping has revealed that the majority of S. aureus strains express either capsular polysaccharides type 5 (CP5) or type 8 (CP8).

Previous studies at Pfizer Inc. involved the preparation of conjugates of the purified native CPs derived from fermentation with protein carriers. Characterization of the activated products derived from purified native CPs by spectroscopic methods proved to be difficult owing to their large size. It was also noted that over activation and side reactions taking place during the conjugation process could lead to a loss of the epitopes required to achieve high immunogenicity of CP conjugate vaccines. This, in turn, can lead to the failure of the vaccine candidates in clinical trials.

This thesis details the total syntheses of oligosaccharides structurally related to the repeating units of capsular polysaccharides S. aureus type 5 and 8. Our targets including two disaccharides, two trisaccharides and a hexasaccharide that will be studied by our collaborators at Pfizer Inc. to understand chemical activation for conjugation to the experimental carrier proteins. The improved understanding of the conjugation process will, in turn, lead to a more controlled, predictable, and reproducible outcome of polysaccharide conjugations. The additional potential outcome of this synthetic study is the development of alternative treatments to fight S. aureus infections.

Available for download on Thursday, April 30, 2020

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