Abstract
A promising approach in combatting infections from antibiotic resistant bacteria/fungi is using therapeutic monoclonal antibodies (mAbs) that can bind the outer surfaces of microbes. We have developed a synthetic vaccine platform that can rapidly generate mAbs against surface glycans from desired strains, such as lipopolysaccharides and capsular polysaccharides. To create therapeutic antibodies against Ruminococcus gnavus, Burkholderia multivorans, and Staphylococcus aureus, we synthesize glycan antigens from each strain that are necessary for use in our glycoconjugate vaccine platform. Blooms of the Gram-positive bacterium Ruminococcus gnavus have been correlated with inflammatory bowel disease, and recently a polysaccharide produced by this organism was shown to stimulate release of inflammatory cytokines. This stimulation was proposed to signal through toll-like receptor 4. We have synthesized the pentasaccharide repeating unit of this polysaccharide and showed that it stimulates TNF-α and IL-6 release from bone marrow-derived dendritic cells in a TLR4-dependent manner. A related glycan does not stimulate significant cytokine release, demonstrating TLR4 selectivity in glycan recognition. Ceragenins are a class of antimicrobials that have broad-spectrum activity against many antimicrobial resistant strains of fungi, Gram-negative bacteria, and Gram-positive bacteria. Previous work has shown that ceragenins can tolerate large structural modifications without loss of activity, such as incorporation of long polyethylene glycol linkers and other domains with selective binding activities. Here we perform structure activity relationship studies of the tail domain of ceragenins to bind hydroxyapatite to combat bone infection, copper for preventing implant related infections, and as a bioresorbable antimicrobial for use in bioresorbable medical devices.
Degree
PhD
College and Department
Computational, Mathematical, and Physical Sciences; Chemistry and Biochemistry
Rights
https://lib.byu.edu/about/copyright/
BYU ScholarsArchive Citation
Gubler, Shawn, "Synthesis of Glycan Antigens for Therapeutic Antibodies and Glycoconjugate Vaccines, Synthesis of an Inflammatory Pentasaccharide, and Design and Synthesis of Ceragenins for use in Medical Devices and Osteomyelitis" (2024). Theses and Dissertations. 10662.
https://scholarsarchive.byu.edu/etd/10662
Date Submitted
2024-12-12
Document Type
Dissertation
Handle
http://hdl.lib.byu.edu/1877/etd13499
Keywords
ceragenin, CSA, mAb, conjugate vaccine, synthesis, Rumminococcus gnavus, Burkholderia multivorans, Staphylococcus aureus
Language
english