Mode of action of linear amphipathic α-helical antimicrobial peptides

Ziv, Oren; Shai, Yechiel

doi:10.1002/(sici)1097-0282(1998)47:6<451::aid-bip4>3.0.co;2-f

Cited by 757 publications

(424 citation statements)

References 145 publications

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“…39 The peptide retention times (R t values) are shown in Table III. As expected, the tetra-substituted Ala-to-Leu peptide 6K-F17-4L 8,11,13,16 was retained the longest on the HPLC column among the Ala-substituted series, followed by triple, double, hairpin (SPGS-34), mono-Leu, cyclic, and nonsubstituted peptides, followed finally the least hydrophobic Ala-to-Asp substituted-7K-F18-1D 17 . Magainin II amide showed the longest R t value, reading out as the most hydrophobic peptide among those tested.…”

Section: Hydrophobicitysupporting

confidence: 73%

“…4L 8,11,13,16 , displayed the highest hemolytic profile (up to 50%), while magainin II amide showed almost complete hemolysis at all concentrations tested. Isomers with the same number of Ala-to-Leu mutations showed similar but not identical activities; for example, 6K-F17-2L 11,13 showed the lowest hemolytic activity among double-substituted isomers.…”

Section: Two Thresholds In Cap-membrane Interactions 365mentioning

confidence: 97%

“…6 Highly positively-charged antimicrobial peptides, termed cationic antimicrobial peptides (CAPs), exist predominantly as random coil structures in solution, but adopt folded secondary structures in hydrophobic environments, typically with amphipathic helical character wherein charged residues are grouped on one face of the helix, while hydrophobic residues are grouped on the opposite face. 8 In general, CAPs are active in the low-medium micromolar range and show little target or L-vs. D-residue specificity (enantiomers usually exhibit similar or two-fold higher activity when compared with their L-counterparts), indicating that they interact with achiral components of the cell membrane 9,10 through a mechanism of physical disruption. CAPs likely attach in an asymmetrical manner from the outer leaflet of the biological membrane, and penetrate it, physically disrupting the bacterial cellular bilayer, leading to lysis and eventually cell death.…”

Section: Introductionmentioning

confidence: 99%

“…14 Biophysical studies have demonstrated that there are some general nonreceptor-mediated mechanisms responsible for peptide antimicrobial activity, which appear to involve permeabilization of phospholipid bilayer membranes via ''barrel-stave,'' ''toroidal pore,'' or ''carpet detergent-like'' arrangements. 3,8,11,15 Since the majority of antimicrobial peptides are positively charged at physiological pH, while outer leaflets of mammalian and bacterial plasma membranes are totally neutral and anionic, respectively, the mechanisms of their antimicrobial and hemolytic activities might differ in detail.…”

Section: Introductionmentioning

confidence: 99%

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Membrane interactions of designed cationic antimicrobial peptides: The two thresholds

2008

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ABSTRACT:Novel cationic antimicrobial peptides (CAPs) designed in our lab-typified by sequences such as KKKKKKAAX-AAXAAXAA-NH 2 , where X 5 Phe/Trp-display high antibacterial activity but exhibit little or no hemolytic activity towards human red blood cells even at high doses.To clarify the mechanism of their selectivity for bacterial versus mammalian membranes and to increase our understanding of the relationships between primary sequence and bioactivity, a library of derivatives was prepared by increasing segmental hydrophobicity, in which systematic substitutions of Ala for two, three, or four Leu residues were made. Conformationally constrained dimeric and cyclic derivatives were also synthesized. The peptides were examined for activity against pathogenic bacteria (Pseudomonas aeruginosa),

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Section: Hydrophobicitysupporting

confidence: 73%

Section: Two Thresholds In Cap-membrane Interactions 365mentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Membrane interactions of designed cationic antimicrobial peptides: The two thresholds

2008

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“…This implies that the degree of bilayer disruption must be controlled by the depth of helix insertion or variation in local peptide concentration and aggregation state. The importance of aggregation in bilayer disruption by surface oriented peptides has already been recognized, and the general model of activity for these peptides postulates that toroidal pores, or other membrane defects, arise in areas of high local peptide concentration that form transiently through diffusion of the peptide on the bilayer surface (9,54).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37

2003

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LL-37 is an amphipathic, R-helical, antimicrobial peptide. 15 N chemical shift and 15 N dipolarshift spectroscopy of site-specifically labeled LL-37 in oriented lipid bilayers indicate that the amphipathic helix is oriented parallel to the surface of the bilayer. This surface orientation is maintained in both anionic and zwitterionic bilayers and at different temperatures and peptide concentrations, ruling out a barrelstave mechanism for bilayer disruption by LL-37. In contrast, electrostatic factors, the type of lipid, and the presence of cholesterol do affect the extent to which LL-37 perturbs the lipids in the bilayer as observed with 31 P NMR. The 31 P spectra also show that micelles or other small, rapidly tumbling membrane fragments are not formed in the presence of LL-37, excluding a detergent-like mechanism. LL-37 does increase the lamellar to inverted hexagonal phase transition temperature of both PE model lipid systems and Escherichia coli lipids, demonstrating that it induces positive curvature strain in these environments. These results support a toroidal pore mechanism of lipid bilayer disruption by LL-37.

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Antimicrobial Peptides

Mor

2001

Kirk-Othmer Encyclopedia of Chemical Technology

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Antimicrobial peptides (AMPs), important effector molecules of the innate immune system, also provide templates for designing novel antibiotics. Protegrin, an especially potent AMP found in porcine leukocytes, was recently shown to form octameric transmembrane pores. We have employed a combination of experiments and models spanning length scales from the atomistic to the cellular level in order to elucidate the microbicidal mechanism of protegrin. Comparison of the modeling and experimental data suggests that approximately 10-100 protegrin pores are necessary to explain the observed rates of potassium leakage and Escherichia coli death in exponential-phase bacteria. The kinetics of viability loss suggest that bacterial death results largely from uncontrolled ion exchange processes and decay of transmembrane potential. However, ion exchange processes alone cannot account for the experimentally observed cell swelling and osmotic lysis-a redundant ''overkill'' mechanism most likely to occur in locales with high protegrin concentrations. Although our study is limited to protegrin and E. coli, the timeline of events described herein is likely shared by other AMPs that act primarily by permeabilizing microbial membranes. This work provides many of the missing links in describing antimicrobial action, as well as providing a quantitative connection between several previous experimental and simulation studies of protegrin.

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Mode of action of linear amphipathic α-helical antimicrobial peptides

Cited by 757 publications

References 145 publications

Membrane interactions of designed cationic antimicrobial peptides: The two thresholds

Membrane interactions of designed cationic antimicrobial peptides: The two thresholds

Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37

Antimicrobial Peptides

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