1. Academic Validation
  2. Tailoring cytotoxicity of antimicrobial peptidomimetics with high activity against multidrug-resistant Escherichia coli

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

  • J Med Chem. 2014 Apr 10;57(7):2864-73. doi: 10.1021/jm401335p.
Rasmus D Jahnsen 1 Anne Sandberg-Schaal Karina Juul Vissing Hanne Mørck Nielsen Niels Frimodt-Møller Henrik Franzyk
Affiliations

Affiliation

  • 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Abstract

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.

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