ABSTRACT
In light of the era of microbial drug resistance, the current study aimed to better understand the relationships between sequence, higher-order structure, and mechanism of action for five designed peptides against multidrug-resistant (MDR) pathogens. All peptides studied were 15 residues long, were polycationic, adopted alpha-helical structures within hydrophobic environments (excluding the d-amino acid-substituted peptide MA-d), and contained N-terminal glycine residues, a novel antimicrobial peptide (AMP) design principle. Increasing hydrophobicity enhanced MICs (≤500 µg/ml to ≤7.4 µg/ml) without significantly increasing hemolytic activity (18% maximum hemolysis at 3,400 µg/ml). To the best of our knowledge, this is the first study to have successfully adapted and used a transmission electron microscopy (TEM) immunogold method to investigate the mechanism of action of short (â¼15 residues long) AMPs within bacteria. We propose a "floodgate" mechanism to possibly explain membrane deformation and the relative absence of membrane-associated peptides 10 h into incubation.
