Abstract
A major barrier to the use of antimicrobial peptides as antibiotics is the toxicity or ability to lyse eukaryotic cells. In this study, a 26-residue amphipathic α-helical antimicrobial peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) was used as the framework to design a series of D- and L-diastereomeric peptides and study the relationships of helicity and biological activities of α-helical antimicrobial peptides. Peptide helicity was measured by circular dichroism spectroscopy and demonstrated to correlate with the hydrophobicity of peptides and the numbers of D-amino acid substitutions. Therapeutic index was used to evaluate the selectivity of peptides against prokaryotic cells. By introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix, the hemolytic activity of peptide analogs have been significantly reduced. Compared to the parent peptide, the therapeutic indices were improved of 44-fold and 22-fold against Gram-negative and Gram-positive bacteria, respectively. In addition, D- and L-diastereomeric peptides exhibited lower interaction with zwitterionic eukaryotic membrane and showed the significant membrane damaging effect to bacterial cells. Helicity was proved to play a crucial role on peptide specificity and biological activities. By simply replacing the hydrophobic or the hydrophilic amino acid residues on the non-polar or the polar face of these amphipathic derivatives of the parent peptide with D-amino acids, we demonstrated that this method could have excellent potential for the rational design of antimicrobial peptides with enhanced specificity.
Highlights
In recent years, resistant superbugs have become a great concern in public health due to the extensive clinical use of classical antibiotics and prompting an urgent need for a new class of antibiotics (Oyston et al, 2009)
By replacing the hydrophobic or the hydrophilic amino acid residues on the non-polar or the polar face of these amphipathic derivatives of the parent peptide with D-amino acids, we demonstrated that this method could have excellent potential for the rational design of antimicrobial peptides with enhanced specificity
A 26-residue amphipathic α-helical antimicrobial peptide of A12L/A20L from the previous studies (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide, named as peptide P ) with a strong α-helical structure (Chen et al, 2007) was used as a framework to design a series of D- and L-diastereomeric peptides and study the relationships of helicity and biological activities of α-helical antimicrobial peptides
Summary
Resistant superbugs have become a great concern in public health due to the extensive clinical use of classical antibiotics and prompting an urgent need for a new class of antibiotics (Oyston et al, 2009). Compared to the traditional antibiotics, cationic antimicrobial peptides (AMPs) exhibit several unique characteristics, including the ability to rapidly kill target cells, broad spectrum activity against serious antibiotic-resistant pathogens in the clinic, and the relative difficulty in selecting resistant mutants in vitro (Jenssen et al, 2006; Huang et al, 2010b). Based on the “barrel-stave” model and the “carpet” model, Chen et al proposed a “membrane discrimination” model for AMPs whose sole target is the biomembrane, and the peptide specificity to eukaryotic or prokaryotic cells depends upon the compositional difference in the lipids of membranes (Chen et al, 2005; Chen et al, 2007). The precise mechanism of action of AMPs has not been fully deciphered, it is believed that the cytoplasmic membrane is the main
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