TY - JOUR

T1 - Alternating Cationic-Hydrophobic Peptide/Peptoid Hybrids

T2 - Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity

AU - Frederiksen, Nicki

AU - Hansen, Paul R

AU - Zabicka, Dorota

AU - Tomczak, Magdalena

AU - Urbas, Malgorzata

AU - Domraceva, Ilona

AU - Björkling, Fredrik

AU - Franzyk, Henrik

N1 - © 2020 Wiley-VCH GmbH.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1002/cmdc.202000526

DO - 10.1002/cmdc.202000526

M3 - Journal article

C2 - 33029927

VL - 15

SP - 2544

EP - 2561

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 24

ER -