Journal article
Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: Synthesis, antibacterial evaluation and preliminary mechanism of action studies
European Journal of Medicinal Chemistry, Vol.168, pp.386-404
2019
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.
Details
- Title
- Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: Synthesis, antibacterial evaluation and preliminary mechanism of action studies
- Authors/Creators
- A.J. Tague (Author/Creator)P. Putsathit (Author/Creator)K.A. Hammer (Author/Creator)S.M. Wales (Author/Creator)D.R. Knight (Author/Creator)T.V. Riley (Author/Creator)P.A. Keller (Author/Creator)S.G. Pyne (Author/Creator)
- Publication Details
- European Journal of Medicinal Chemistry, Vol.168, pp.386-404
- Publisher
- Elsevier Masson SAS
- Identifiers
- 991005540513607891
- Copyright
- © 2019 Elsevier Masson SAS
- Murdoch Affiliation
- School of Veterinary and Life Sciences
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 2 Chemistry
- 2.190 Surfactants, Lipid Bilayers & Antimicrobial Peptides
- 2.190.857 Antimicrobial Peptides
- Web Of Science research areas
- Chemistry, Medicinal
- ESI research areas
- Chemistry