Helicity Modulation Improves the Selectivity of Antimicrobial Peptoids

Abstract

The modulation of conformational flexibility in antimicrobial peptides (AMPs) has been investigated as a strategy to improve their efficacy against bacterial pathogens while reducing their toxicity. Here, we synthesized a library of helicity-modulated antimicrobial peptoids by the position-specific incorporation of helix-inducing monomers. The peptoids displayed minimal variations in hydrophobicity, which permitted the specific assessment of the effect of conformational differences on antimicrobial activity and selectivity. Among the moderately helical peptoids, the most dramatic increase in selectivity was observed in peptoid 17, providing more than a 20-fold increase compared to fully helical peptoid 1. Peptoid 17 had potent broad-spectrum antimicrobial activity that included clinically isolated multi-drug-resistant pathogens. Compared to pexiganan AMP, 17 showed superior metabolic stability, which could potentially reduce the dosage needed, alleviating toxicity. Dye-uptake assays and high-resolution imaging revealed that the antimicrobial activity of 17 was, as with many AMPs, mainly due to membrane disruption. However, the high selectivity of 17 reflected its unique conformational characteristics, with differential interactions between bacterial and erythrocyte membranes. Our results suggest a way to distinguish different membrane compositions solely by helicity modulation, thereby improving the selectivity toward bacterial cells with the maintenance of potent and broad-spectrum activity.

Lung SPLUNC1 Peptide Derivatives in the Lipid Membrane Headgroup Kill Gram-Negative Planktonic and Biofilm Bacteria

“…In addition, the lowest MIC values were linearly correlated with the highest helicities (Figure ). These efficacy results agree with previously obtained experimental results using other peptides, which showed a correlation between higher helicity and higher bacterial killing efficacy. − …”

The Potential of Modified and Multimeric Antimicrobial Peptide Materials as Superbug Killers

“…More recently, the role of helicity was further explored using peptoid 1, a peptoid (residues with the side-chain moiety connected to the backbone nitrogen rather than the α-carbon of the amino acid) mimic of magainin 2 ( Patch and Barron, 2003 ). This peptoid was made using N-(4-aminobutyl)-glycine ( N Lys), a peptoid analogue of lysine (Lys (K)), and (S)-N-(1-phenylethyl)amine ( N spe), an analogue of phenylalanine (Phe (F)) that acts as a helix inducer ( Nam et al, 2020 ). Peptoid 1 was reported to be fully helical and a non-helical peptoid 2 was also created by substituting all N spe with N-(phenylmethyl)glycine ( N pm).…”

Evaluation of the Antimicrobial Properties of a Natural Peptide from Vespa mandarinia Venom and Its Synthetic Analogues as a Possible Route to Defeat Drug-Resistant Microbes

“…It has been noted that VM-3Y had a prominent selectivity index and low haemolytic activity. This result may suggest that the increase in the helicity of VM-3Y enhanced the selectivity between erythrocyte and bacterial membranes [ 39 ]. However, for VM-3G, which also exhibited an enhancement of helicity, the flexible structure may lose control over of all types of lipid bilayers and the hinge at the third position may be a constrained structure for membrane interaction.…”