UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis of peptidoglycan peptides for DNA aptamer selection Zhang, Wenxuan


Gram-positive bacteria possess a thick layer of peptidoglycan outside the cell membrane that is rigidified through crosslinks between neighboring peptide chains on the polysaccharide structure. Vancomycin, a glycopeptide antibiotic, is effective at inhibiting the growth of Gram-positive bacteria by preventing the formation of crosslinks. The molecular basis of vancomycin’s action is tight binding to a cell wall peptide precursor that terminates in D-Ala-D-Ala. In vancomycin resistant bacteria, the D-Ala-D-Ala linkage is replaced by D-Ala-D-Lac and the loss of a hydrogen bond to the amide NH accounts for a 1000-fold loss in potency. In this research, we hope to generate DNA aptamers that will serve as an alternative to vancomycin and bind tightly to the peptidoglycan peptides. For DNA aptamer selection, two target compounds are synthesized. One molecule (Target 2) mimics the cell wall peptide precursor of vancomycin sensitive bacteria that terminates in L-Lys-D-Ala-D-Ala. Another molecule (Target 3) mimics the cell wall peptide precursor of vancomycin-resistant bacteria that terminates in L-Lys-D-Ala-D-Lac. This molecule will also be used to find catalytic unnatural DNA sequences (bearing primary amine groups) that can trans-amidate and displace the terminal lactate moiety. This will serve to form an agent that inactivates peptidoglycan biosynthesis of vancomycin resistant bacteria by forming a covalent linkage.

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