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

Andrew J. Tague, Papanin Putsathit, Katherine A. Hammer, Steven M. Wales, Daniel R. Knight, Thomas V. Riley, Paul A. Keller, Stephen G. Pyne

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 pharmaco-phore. 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 mu g/mL) and Gram-negative (Escherichia coli - MIC = 4 mu g/mL) pathogenic bacteria. (C) 2019 Elsevier Masson SAS. All rights reserved.

Original languageEnglish
Pages (from-to)386-404
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Volume168
DOIs
Publication statusPublished - 15 Apr 2019

Cite this

Tague, Andrew J. ; Putsathit, Papanin ; Hammer, Katherine A. ; Wales, Steven M. ; Knight, Daniel R. ; Riley, Thomas V. ; Keller, Paul A. ; Pyne, Stephen G. / Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles : synthesis, antibacterial evaluation and preliminary mechanism of action studies. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 168. pp. 386-404.
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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 pharmaco-phore. 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 mu g/mL) and Gram-negative (Escherichia coli - MIC = 4 mu g/mL) pathogenic bacteria. (C) 2019 Elsevier Masson SAS. All rights reserved.",
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Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles : synthesis, antibacterial evaluation and preliminary mechanism of action studies. / Tague, Andrew J.; Putsathit, Papanin; Hammer, Katherine A.; Wales, Steven M.; Knight, Daniel R.; Riley, Thomas V.; Keller, Paul A.; Pyne, Stephen G.

In: European Journal of Medicinal Chemistry, Vol. 168, 15.04.2019, p. 386-404.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles

T2 - synthesis, antibacterial evaluation and preliminary mechanism of action studies

AU - Tague, Andrew J.

AU - Putsathit, Papanin

AU - Hammer, Katherine A.

AU - Wales, Steven M.

AU - Knight, Daniel R.

AU - Riley, Thomas V.

AU - Keller, Paul A.

AU - Pyne, Stephen G.

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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 pharmaco-phore. 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 mu g/mL) and Gram-negative (Escherichia coli - MIC = 4 mu g/mL) pathogenic bacteria. (C) 2019 Elsevier Masson SAS. All rights reserved.

AB - 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 pharmaco-phore. 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 mu g/mL) and Gram-negative (Escherichia coli - MIC = 4 mu g/mL) pathogenic bacteria. (C) 2019 Elsevier Masson SAS. All rights reserved.

KW - Antibacterial

KW - Peptidomimetic

KW - Biaryl cationic amphiphiles

KW - Membrane depolarization

KW - Amphipathic

KW - AZIDE-ALKYNE CYCLOADDITION

KW - ANTIMICROBIAL PEPTIDOMIMETICS

KW - RESISTANCE

KW - MIMICS

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DO - 10.1016/j.ejmech.2019.02.013

M3 - Article

VL - 168

SP - 386

EP - 404

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -