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

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.

Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties

“…46–47% MeCN (for 5 and 6 ) induced a pronounced rise in hemolysis from 0.6% to 15.7% at 400 µg/mL. This finding is in accordance with a recent report on a wide range of peptoid/peptide hybrids [ 32 ].…”

“…Intriguingly, a similar analysis of the hydrophobicity of the present 11 peptidomimetics (all having an alternative peptide/β-peptoid design with cationic amino acids) revealed that they cover a wide range of hydrophobicity (from 40.2% to 51.6% MeCN ( Table 3 ) when using the same setup as for analytical HPLC [ 32 ]). Moreover, several compounds display acceptable hemolytic properties (i.e., less than 10% hemolysis at 400 µg/mL, corresponding to a ~100-fold higher concentration than the typical MIC values against E. faecium ), while other analogues possess considerable hemolytic activity ( Table 3 ).…”

“…While the hydrophobicity of small molecules is typically estimated by their partition coefficients, e.g., the log D values, the relative retention in reverse-phase HPLC (RP-HPLC) constitutes a more appropriate measure of hydrophobicity for very polar and highly cationic peptides and peptidomimetics [ 15 , 18 , 31 , 32 ]. Recently, within a large set of peptidomimetics, resembling those in the present study, we identified a correlation between hydrophobicity, expressed as percent acetonitrile (%MeCN) at peak elution in analytical RP-HPLC, antibacterial activity, and hemolytic properties [ 32 ]. Here, it proved possible to identify a hydrophobicity threshold above which cell selectivity was partially lost (i.e., >10% hemolysis at 400 µg/mL) for 12-mer α-peptoid/peptide hybrids displaying α-peptoid lysine-like cationic residues and hydrophobic α-amino acids.…”

“…For that subclass, this threshold (43.9% MeCN) coincided with the hydrophobicity threshold required to confer potent activity against E. faecalis . In contrast, for Gram-negative bacteria, the latter lower hydrophobicity thresholds for antibacterial activity were considerably lower, implying that an appropriate design window for compounds with intermediate hydrophobicity existed [ 32 ]. These previous results indicated that it might be quite difficult to identify compounds displaying anti-enterococcal activity while possessing satisfactory cell selectivity.…”

Peptide/β-Peptoid Hybrids with Ultrashort PEG-Like Moieties: Effects on Hydrophobicity, Antibacterial Activity and Hemolytic Properties

“…Peptide/peptoid hybrids constitute an interesting class of peptidomimetics, and among such oligomers with an alternating cationic-hydrophobic design we previously identified subclasses possessing a superior pharmacological profile as compared to the corresponding peptides and peptoid homooligomers [13]. In subsequent studies, peptide/peptoid hybrid oligomers were found to possess potent activity against Gramnegative pathogens, e.g., Escherichia coli [14][15][16][17], Pseudomonas aeruginosa [15][16][17][18], and Acinetobacter baumannii [16,18] as well as toward Gram-positive pathogens, e.g., Staphylococcus aureus [15,17,18] and Enterococcus faecium [18].…”