Date of Award
Master of Science
Dr. Elizabeth Gillies
In recent years, there have been increasing numbers of bacterial strains emerging that are resistant to the currently available antibiotics. In the search for new antibiotics, attention has been focused on natural antimicrobial peptides that act by selectively disrupting the membranes of bacterial cells, a mechanism that is thought to be non- conducive to the development of resistance. It is desirable to mimic the structures and activities of these peptides, while introducing properties such as resistance to proteolytic degradation, which make molecules more ideal for development as drugs. Described here is the design and synthesis of P-strand mimetic oligomers based on alternating a-amino acids and azacyclohexenone units that segregate cationic lysine and hydrophobic valine side chains on opposite faces of the p-strand. *HNMR dilution studies demonstrated that despite the incorporation of alternating D- and L-amino acids in order to obtain facial amphiphilicity, these oligomers are capable of dimerizing to P-sheet mimics in a manner similar to the oligomers containing all L-amino acids. The ability of the molecules to disrupt phospholipid vesicles mimicking the membranes o f both bacterial and mammalian cells was investigated using a fluorescent dye leakage assay. Several of the oligomers were found to exhibit activity and selectivity for the bacterial over mammalian membranes. Overall, these studies demonstrate the promise of this class of molecules for the development of new potential antibiotics, and provide information on the structural features that are important for activity.
Watson, Jessica L., "Development of Amphipathic Beta-Strand Mimics as Potential Membrane Active Antibiotics" (2009). Digitized Theses. 3908.