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Key Residues in Octyl-Tridecaptin A1 Analogues Linked to Stable Secondary Structures in the Membrane

Authors

  • Stephen A. Cochrane,

    1. Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta, T6G 2G2 (Canada)
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  • Dr. Brandon Findlay,

    1. Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta, T6G 2G2 (Canada)
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  • Dr. John C. Vederas,

    Corresponding author
    1. Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta, T6G 2G2 (Canada)
    • John C. Vederas, Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta, T6G 2G2 (Canada)===

      Elaref S. Ratemi, Department of Chemical and Process Engineering Technology, Jubail Industrial College, Jubail Industrial City, 31961, P. O. Box 10099 (Kingdom of Saudi Arabia)===

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  • Dr. Elaref S. Ratemi

    Corresponding author
    1. Department of Chemical and Process Engineering Technology, Jubail Industrial College, Jubail Industrial City, 31961, P. O. Box 10099 (Kingdom of Saudi Arabia)
    • John C. Vederas, Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta, T6G 2G2 (Canada)===

      Elaref S. Ratemi, Department of Chemical and Process Engineering Technology, Jubail Industrial College, Jubail Industrial City, 31961, P. O. Box 10099 (Kingdom of Saudi Arabia)===

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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.

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