Action of Antimicrobial Peptides: Two-State Model

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Abstract
The argument and experimental evidence are presented for a two-state model that explains the action of both helical and β-sheet antimicrobial peptides after they bind to the plasma membranes of cells. Each peptide has two distinct physical states of binding to lipid bilayers. At low peptide-to-lipid ratios (P/L), the peptide tends to adsorb in the lipid headgroup region in a functionally inactive state. At a P/L above a threshold value P/L*, the peptide forms a multiple-pore state that is lethal to a cell. The susceptibility of a cell to an antimicrobial peptide depends on the value of P/L* that is determined by the lipid composition of the cell membrane. This model provides plausible explanations for the experimental findings that the susceptibility of different bacteria to a peptide is not directly correlated to its binding affinity, different peptides preferentially kill different pathogens, and peptides exhibit varying levels of lytic activity against different eukaryotic cells.