Mechanistic Studies of Antimicrobial Peptides in Lipid Membranes

  • Author / Creator
    Isaac Antwi
  • Antibiotics with unexplored mechanisms are needed to fight the alarming rise in antimicrobial resistance. Antimicrobial compounds targeting peptidoglycan precursor lipid II, the Achilles’ heel of bacteria, can be a suitable template. Therefore, structural studies of membrane mimetic models may provide insights regarding peptide-lipid interactions at atomic resolution. Highlighted in this thesis are the syntheses of peptidoglycan precursor lipid II and its analogues as well as various phospholipids, with the aim of using these synthetic analogues for structural studies on peptides. Some smaller compounds with antimicrobial properties are also explored in this thesis.
    Tridecaptin A1 is part of a class of peptides that are potent against Gram-negative bacteria. They are known to bind to lipid II, the same peptidoglycan precursor targeted by certain other antimicrobial peptides. In order to better understand the interaction between tridecaptin A1 and its target, insights into the physiological mode of action require a liposomal solvent to mimic the native setting. I addressed this by synthesizing native Gram-negative lipid II and tridecaptin A1 containing fully labelled amino acids which appear to be in close proximity to its lipid II target. Solid state NMR spectroscopic studies of the peptide and lipid II in liposomes was measured to understand how tridecaptin interacts with the cell wall precursor lipid II.
    Cycloalanopine is a cyclic opine with reported antimicrobial activity identified in 2019. I synthesized a series of analogues to determine the stereochemistry of the active cycloalanopine. Additionally, a series of cycloalanopine analogues were also synthesized and a cyclic glycine derivative was identified with activity against both Gram-negative and Gram-positive bacteria.
    With our ongoing research in understanding the interaction of tridecaptin A1 and its targets, I synthesized a series of membrane mimic phospholipids with heteroatoms replacing specific methylene groups along the lipid tail of dodecylphosphocholine (DPC). This approach was used to understand how peptides can interact within the lipid membrane, by analyzing the influence heteroatoms exert at different positions along the lipid tail had on the structure of tridecaptin A1 in these micelles. This was accomplished with the use of solution state NMR spectroscopy. This idea will be extended to other membrane-interacting antimicrobial peptides, like leucocin A, and so I synthesized undeuterated analogues of DPC to enhance further studies.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.