Abstract
The self-assembly and antimicrobial activity of two novel arginine-capped bola-amphiphile peptides, namely RA6R and RA9R (R, arginine; A, alanine) are investigated. RA6R does not self-assemble in water due to its high solubility, but RA9R self-assembles above a critical aggregation concentration into ordered nanofibers due to the high hydrophobicity of the A9block. The structure of the RA9R nanofibers is studied by cryogenic transmission electron microscopy (cryo-TEM) and small-angle X-ray scattering (SAXS). Circular dichroism spectroscopy shows that both RA6R and RA9R adopt coil conformations in water at low concentration, but only RA9R adopts a β-sheet conformation at high concentration. SAXS and differential scanning calorimetry are used to study RA6R and RA9R interactions with a mixed lipid membrane that models a bacterial cell wall, consisting of multilamellar 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol/1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine vesicles. Cytotoxicity studies show that RA6R is more cytocompatible than RA9R. RA6R has enhanced activity against the Gram-negative pathogen P. aeruginosa at a concentration where viability of mammalian cells is retained. RA9R has little antimicrobial activity, independently of concentration. Our results highlight the influence of the interplay between relative charge and hydrophobicity on the self-assembly, cytocompatibility, and bioactivity of peptide bola-amphiphiles.
Highlights
The increasing occurrence of antibiotic resistant pathogens is leading to an urgent need to discover or design novel therapeutics to combat this issue
We first characterize the self-assembly of RA6R and RA9R in water using Circular Dichroism (CD), FTIR, XRD, smallangle X-ray scattering (SAXS), and cryo-TEM
We study the interaction of RA6R and RA9R with model bacterial membrane walls represented by DPPG/DPPE multilamellar vesicles
Summary
The increasing occurrence of antibiotic resistant pathogens is leading to an urgent need to discover or design novel therapeutics to combat this issue. One important class of therapeutics is antimicrobial peptides. Antimicrobial peptides are attractive since many are expressed naturally, and this can be used as a basis for novel compounds and due to their ease of biofunctionalization and biocompatibility.[1−3] Many organisms, for example, fungi, have naturally evolved host defense antimicrobial peptides, which can be used as actives themselves, or form the basis of designed synthetic materials. Antimicrobial peptides with the ability to self-assemble may be active without the need for carrier molecules. A class of peptide with strong self-assembly properties are surfactant-like peptides (SLPs), initially developed by Zhang et al.[4−7] These peptides are short, consisting of a one or two charged residue headgroup, with a longer hydrophobic sequence as a tail group. Peptides with various cationic and anionic headgroups, and different hydrophobic amino acid tail
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