title: Probing the "charge cluster mechanism" in amphipathic helical cationic antimicrobial peptides.
abstract: Clustering of anionic lipids away from zwitterionic ones by cationic antimicrobial agents has recently been established as a mechanism of action of natural small, flexible peptides as well as non-natural synthetic peptide mimics. One of the largest classes of antimicrobial peptides consists of peptides that form cationic amphipathic helices on membranes and whose toxic action is dependent on the formation of pores in the membrane or through the "carpet" mechanism. We have evaluated the role of anionic lipid clustering for five of these peptides, i.e., MSI-78, MSI-103, MSI-469, MSI-843, and MSI-1254, with different sequences and properties. We determined whether these amphipathic helical cationic antimicrobial peptides cluster anionic lipids from zwitterionic ones and if this property is related to the species specificity of their toxicity. All five of these peptides were capable of lipid clustering, in contrast to the well-studied amphipathic helical antimicrobial peptide, magainin 2, which does not. We ascribe this difference to the lower density of positive charges in magainin 2. Peptides that efficiently cluster anionic lipids generally have a ratio of MIC for Staphylococcus aureus to that for Escherichia coli of >1. The addition of an N-terminal octyl chain did not preclude anionic charge clustering, although the ratio of MIC for S. aureus to that for E. coli was somewhat lowered. In most Gram-positive bacteria, there is a predominance of anionic lipids in the cytoplasmic membrane. In Gram-negative bacteria, however, clustering of anionic lipids away from zwitterionic ones is emerging as an important contributing mechanism of bacterial toxicity for some antimicrobial agents.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Epand
authors.forename: W Lee
authors.initials: WL
authors.lastname: Maloy
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.forename: Richard M
authors.initials: RM
authors.lastname: Epand
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability; D004926:Escherichia coli / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D010455:Peptides
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