Antimicrobial peptides are part of the innate immune system and have been an area of great interest due to their small size and broad-spectrum activity. Numerous studies on antimicrobial peptides from a variety of sources including humans, reptiles, insects, and other mammals have shown no conserved sequences but conserved gene including amphiphilicity, tendency to form Alpha helical structures, net positive charge, and a propensity to interact with lipid membranes. The proposed mechanism of action is through disruption of the bacterial membrane. This study investigates the peptide C 18 G, derived from a human platelet protein, by varying the hydrophobic amino acids in the sequence. The parent peptide was composed of solely leucine residues as the hydrophobics which were replaced with phenylalanine, isoleucine, valine, and the nonproteinogenic amino acid 2-aminoisobutyric acid.  Peptide affinity for model lipid membranes was monitored by tryptophan fluorescence spectroscopy. The structure and topography of the peptide when membrane-bound was investigated using fluorescence quenching and circular dichroism spectroscopy. Antimicrobial efficacy and assays of bacterial membrane permeablization using nonnatural chromogenic substrates were also performed. The parent peptide C 18 G exhibited good binding affinity for an ionic lipid membranes, broad-spectrum antimicrobial activity against both gram-positive and gram-negative species, and a dose dependent ability to permeabilize bacterial membranes Results show that substitution of leucine with phenylalanine had little effect but substitution with isoleucine had a more pronounced effect on both membrane binding and antimicrobial efficacy.  In contrast, substitution of leucine with either valine or 2-aminoisobutyric acid completely inhibited the interactions with the model lipid membranes and significantly reduced the antimicrobial efficacy.

Hydrophobic amino acid SAR in antimicrobial peptides

248th National Meeting (2014)

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