Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids: Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity

Nicki Frederiksen, Paul R Hansen, Dorota Zabicka, Magdalena Tomczak, Malgorzata Urbas, Ilona Domraceva, Fredrik Björkling, Henrik Franzyk

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28 Citations (Scopus)

Abstract

The influence of hydrophobicity on antibacterial activity versus the effect on the viability of mammalian cells for peptide/peptoid hybrids was examined for oligomers based on the cationic Lys-like peptoid residue combined with each of 28 hydrophobic amino acids in an alternating sequence. Their relative hydrophobicity was correlated to activity against both Gram-negative and Gram-positive species, human red blood cells, and HepG2 cells. This identified hydrophobic side chains that confer potent antibacterial activity (e. g., MICs of 2-8 μg/mL against E. coli) and low toxicity toward mammalian cells (<10 % hemolysis at 400 μg/mL and IC50 >800 μg/mL for HepG2 viability). Most peptidomimetics retained activity against drug-resistant strains. These findings corroborate the hypothesis that for related peptidomimetics two hydrophobicity thresholds may be identified: i) it should exceed a certain level in order to confer antibacterial activity, and ii) there is an upper limit, beyond which cell selectivity is lost. It is envisioned that once identified for a given subclass of peptide-like antibacterials such thresholds can guide further optimisation.

Original languageEnglish
JournalChemMedChem
Volume15
Issue number24
Pages (from-to)2544-2561
ISSN1860-7179
DOIs
Publication statusPublished - 2020

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