Mechanistic Studies on Antibiotic Peptides: Lantibiotics and Lipopeptides

• Author / Creator

  Bakhtiary, Alireza

• Antimicrobial peptides (AMPs) are small protein toxins produced by different bacterial strains to fight against closely related strains in their competitive environment. AMPs have been isolated and studied for their interesting properties, including treatment of pathogenic diseases. In this thesis, results of mechanistic studies on AMPs classified as lantibiotic and lipopeptide are discussed. In chapter 2, mechanistic studies on lacticin 3147 will be discussed. Lacticin 3147 is a two peptide lantibiotic (LtnA1 and LtnA2) that displays nanomolar activity against many Gram-positive bacteria. Lacticin 3147 may exert its antimicrobial effect by several mechanisms. Isothermal titration calorimetry experiments showed that only LtnA1 binds to the peptidoglycan precursor lipid II, which could inhibit peptidoglycan biosynthesis. An experimentally supported model of the resulting complex suggests the key binding partners are the C-terminus of LtnA1 and pyrophosphate of lipid II. A combination of in vivo and in vitro assays indicated that LtnA1 and LtnA2 can induce rapid membrane lysis without the need for lipid II binding. However, the presence of lipid II substantially increases the activity of lacticin 3147. Furthermore, studies with synthetic LtnA2 analogues containing either desmethyl- or oxa-lanthionine rings confirm that the precise geometry of these rings is essential for this synergistic activity. In chapter 3, mechanistic studies on tridecaptin A1 (TriA1) and the synthesis of its analogues will be discussed. Tridecaptin A1 belongs to the lipopeptide class of AMPs with selective activity against Gram-negative bacteria. Our studies showed that TriA1 exerts its bactericidal effect by interacting with bacterial cell wall precursor lipid ll to interrupt the proton motive force.

• Subjects / Keywords

  • Lantibiotics
  • Lipopeptides

• Graduation date

  Spring 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3VH5D014

• 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.