title: Key residues in octyl-tridecaptin A1 analogues linked to stable secondary structures in the membrane.
abstract: Tridecaptin A1 is a linear antimicrobial lipopeptide comprised of 13 amino acids, including three diaminobutyric acid (Dab) residues. It displays potent activity against Gram-negative bacteria, including multidrug-resistant strains. Using solid-phase peptide synthesis, we performed an alanine scan of a fully active analogue, octyl-tridecaptin A1 , to determine key residues responsible for activity. The synthetic analogues were tested against ten organisms, both Gram-positive and Gram-negative bacteria. Modification of D-Dab8 abolished activity, and marked decreases were observed with substitution of D-allo-Ile12 and D-Trp5. Circular dichroism showed that octyl-tridecaptin A1 adopts a secondary structure in the presence of model phospholipid membranes, which was weakened by D-Dab8-D-Ala, D-allo-Ile12-D-Ala, and D-Trp5-D-Ala substitutions. The antimicrobial activity of the analogues is directly correlated to their ability to adopt a stable secondary structure in a membrane environment.
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta, T6G 2G2 (Canada).
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Cochrane
authors.forename: Brandon
authors.initials: B
authors.lastname: Findlay
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
authors.forename: Elaref S
authors.initials: ES
authors.lastname: Ratemi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010743:Phospholipids / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; D010743:Phospholipids; C000595730:octyl-tridecaptin A1
keywords: alanine scan; antimicrobial peptides; lipopeptides; structure-activity relationships; tridecaptins