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

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

  • Eur J Med Chem. 2019 Apr 15;168:386-404. doi: 10.1016/j.ejmech.2019.02.013.
Andrew J Tague 1,  Papanin Putsathit 2,  Katherine A Hammer 3,  Steven M Wales 4,  Daniel R Knight 5,  Thomas V Riley 6,  Paul A Keller 7,  Stephen G Pyne 8
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address: [email protected].
  • 2 School of Medical and Health Sciences, Edith Cowan University, Western Australia, 6027, Australia.
  • 3 School of Biomedical Sciences, The University of Western Australia, Western Australia, 6009, Australia.
  • 4 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia.
  • 5 School of Veterinary and Life Sciences, Murdoch University, Western Australia, 6150, Australia.
  • 6 School of Medical and Health Sciences, Edith Cowan University, Western Australia, 6027, Australia; School of Biomedical Sciences, The University of Western Australia, Western Australia, 6009, Australia; School of Veterinary and Life Sciences, Murdoch University, Western Australia, 6150, Australia; PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Western Australia, 6009, Australia.
  • 7 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address: [email protected].
  • 8 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address: [email protected].
PMID: 30831407 DOI: 10.1016/j.ejmech.2019.02.013
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.

Keywords

Amphipathic; Antibacterial; Biaryl cationic amphiphiles; Membrane depolarization; Peptidomimetic.

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