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Composition Effect on Peptide Interaction with Lipids and Bacteria: Variants of C3a Peptide CNY21
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2007 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 92, no 1, 87-98 p.Article in journal (Refereed) Published
Abstract [en]

The effect of peptide hydrophobicity and charge on peptide interaction with model lipid bilayers was investigated for the C3a-derived peptide CNY21 by fluorescence spectroscopy, circular dichroism, ellipsometry, z-potential, and photon correlation spectroscopy measurements. For both zwitterionic and anionic liposomes, the membrane-disruptive potency for CNY21 variants increased with increasing net positive charge and mean hydrophobicity and was completely lost on elimination of all peptide positive charges. Analogous effects of elimination of the peptide positive net charge in particular were found regarding bacteria killing for both Pseudomonas aeruginosa and Bacillus subtilis. The peptides, characterized by moderate helix content both in buffer and when attached to the liposomes, displayed high adsorption for the net positively charged peptide variants, whereas adsorption was nonmeasurable for the uncharged peptide. That electrostatically driven adsorption represents the main driving force for membrane disruption in lipid systems was also demonstrated by a drastic reduction in both liposome leakage and peptide adsorption with increasing ionic strength, and this salt inactivation can be partly avoided by increasing the peptide hydrophobicity. This increased electrolyte resistance translates also to a higher antibacterial effect for the hydrophobically modified variant at high salt concentration. Overall, our findings demonstrate the importance of the peptide adsorption and resulting peptide interfacial density for membrane-disruptive effects of these peptides.

Place, publisher, year, edition, pages
2007. Vol. 92, no 1, 87-98 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-22181DOI: 10.1529/biophysj.106.088161ISI: 000242754300015PubMedID: 17028141OAI: oai:DiVA.org:uu-22181DiVA: diva2:49954
Available from: 2007-01-12 Created: 2007-01-12 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Interaction Between Antimicrobial Peptides and Phospholipid Membranes: Effects of Peptide Length and Composition
Open this publication in new window or tab >>Interaction Between Antimicrobial Peptides and Phospholipid Membranes: Effects of Peptide Length and Composition
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Due to increasing problems with bacterial resistance development, there is a growing need for identifying new types of antibiotics. Antimicrobial peptides constitute an interesting group of substances for this purpose, since they are believed to act mainly by disrupting the bacterial membrane, which is a fast and non-specific mechanism. In order to understand the details on this action simplified phospholipid model membranes based on liposomes, monolayers and bilayers, were employed in this thesis.

By in situ ellipsometry studies on supported lipid bilayers in combination with leakage from liposomes it was found that peptide-induced membrane rupture to a great extent is related to peptide adsorption. The peptide activity and mechanism of action is highly dependent on peptide properties such as length, topology, charge, and hydrophobicity. Electrostatic interactions are crucial for peptide adsorption, whereas α-helix formation is of less importance, demonstrated by the dominating peptide conformation being random coil both in absence and presence of membranes, as investigated by circular dichroism. Comparable effects were observed in both mono- and bilayer systems, showing that formation of transmembrane structures is no prerequisite for membrane rupture by complement-derived peptides. Electrochemical studies on these peptides further demonstrated that hydrophobic interactions facilitate peptide penetration into the membrane, causing defects in close proximity to the peptides, while strong electrostatic interactions arrest the peptide in the headgroup region. Increasing the peptide hydrophobicity, by e.g., tryptophan end-tagging, also increases salt resistance.

Good correlations were found between model membrane investigations and antibacterial activity towards both Gram-negative and Gram-positive bacteria, showing that membrane rupture is a key mechanism of action for the peptides investigated. In addition, for all peptides investigated cell toxicity is low.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 101
Series
Keyword
Adsorption, antibacterial, antimicrobial peptide, bilayer, ellipsometry, electrochemistry, electrostatic interactions, hydrophobicity, liposome, membrane, monolayer, phospholipid, secondary structure, supported bilayer.
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-101989 (URN)978-91-554-7540-6 (ISBN)
Public defence
2009-06-12, B42, Biomedical Center, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-05-18 Created: 2009-04-29 Last updated: 2009-05-18Bibliographically approved

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Ringstad, LovisaMalmsten, Martin

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