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Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies

Journal Article


Abstract


  • Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to divergent derivatization to furnish the amphiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl amphiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 μg/mL) and Gram-negative (Escherichia coli - MIC = 4 μg/mL) pathogenic bacteria.

Authors


  •   Tague, Andrew J.
  •   Putsathit, Papanin (external author)
  •   Hammer, Katherine A. (external author)
  •   Wales, Steven M. (external author)
  •   Knight, Daniel (external author)
  •   Riley, Thomas V. (external author)
  •   Keller, Paul A.
  •   Pyne, Stephen G.

Publication Date


  • 2019

Citation


  • Tague, A. J., Putsathit, P., Hammer, K. A., Wales, S. M., Knight, D. R., Riley, T. V., Keller, P. A. & Pyne, S. G. (2019). Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies. European Journal of Medicinal Chemistry, 168 386-404.

Scopus Eid


  • 2-s2.0-85062208426

Number Of Pages


  • 18

Start Page


  • 386

End Page


  • 404

Volume


  • 168

Place Of Publication


  • France

Abstract


  • Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to divergent derivatization to furnish the amphiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl amphiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 μg/mL) and Gram-negative (Escherichia coli - MIC = 4 μg/mL) pathogenic bacteria.

Authors


  •   Tague, Andrew J.
  •   Putsathit, Papanin (external author)
  •   Hammer, Katherine A. (external author)
  •   Wales, Steven M. (external author)
  •   Knight, Daniel (external author)
  •   Riley, Thomas V. (external author)
  •   Keller, Paul A.
  •   Pyne, Stephen G.

Publication Date


  • 2019

Citation


  • Tague, A. J., Putsathit, P., Hammer, K. A., Wales, S. M., Knight, D. R., Riley, T. V., Keller, P. A. & Pyne, S. G. (2019). Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies. European Journal of Medicinal Chemistry, 168 386-404.

Scopus Eid


  • 2-s2.0-85062208426

Number Of Pages


  • 18

Start Page


  • 386

End Page


  • 404

Volume


  • 168

Place Of Publication


  • France