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Tailoring cytotoxicity of antimicrobial peptidomimetics with high activity against multidrug-resistant Escherichia coli

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DOI

  • Rasmus D Jahnsen
  • Anne Sandberg-Schaal
  • Karina Juul Vissing
  • Hanne Mørck Nielsen
  • Niels Frimodt-Møller
  • Henrik Franzyk
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Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimetics was investigated as a tool for optimizing cell selectivity. A protocol based on dimeric building blocks allowed for efficient synthesis of an array of peptide-peptoid oligomers representing length variation as well as different backbone designs displaying chiral or achiral peptoid residues. Lack of α-chirality in the side chains of the peptoid residues proved to be correlated to reduced cytotoxicity. Furthermore, optimization of the length of these peptidomimetics with an alternating cationic-hydrophobic design was a powerful tool to enhance the selectivity against Gram-negative pathogens over benign mammalian cells. Thus, lead compounds with a high selectivity toward killing of clinically important multidrug-resistant E. coli were identified.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume57
Issue number7
Pages (from-to)2864-73
Number of pages10
ISSN0022-2623
DOIs
Publication statusPublished - 10 Apr 2014

    Research areas

  • Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Antineoplastic Agents, Cell Proliferation, Circular Dichroism, Drug Resistance, Multiple, Gram-Negative Bacteria, Humans, Liposomes, Microbial Sensitivity Tests, Molecular Structure, Neoplasms, Peptidomimetics, Structure-Activity Relationship, Tumor Cells, Cultured

ID: 44853266