Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition
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...
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Uppsala universitet, Institutionen för farmaci
2009
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ndltd-UPSALLA1-oai-DiVA.org-uu-1019892013-01-08T13:05:11ZInteraction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and CompositionengRingstad, LovisaUppsala universitet, Institutionen för farmaciUppsala : Acta Universitatis Upsaliensis2009Adsorptionantibacterialantimicrobial peptidebilayerellipsometryelectrochemistryelectrostatic interactionshydrophobicityliposomemembranemonolayerphospholipidsecondary structuresupported bilayer.PHARMACYFARMACIDue 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. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101989urn:isbn:978-91-554-7540-6Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 101 ; application/pdfinfo:eu-repo/semantics/openAccess |
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English |
format |
Doctoral Thesis |
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topic |
Adsorption antibacterial antimicrobial peptide bilayer ellipsometry electrochemistry electrostatic interactions hydrophobicity liposome membrane monolayer phospholipid secondary structure supported bilayer. PHARMACY FARMACI |
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Adsorption antibacterial antimicrobial peptide bilayer ellipsometry electrochemistry electrostatic interactions hydrophobicity liposome membrane monolayer phospholipid secondary structure supported bilayer. PHARMACY FARMACI Ringstad, Lovisa Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition |
description |
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. |
author |
Ringstad, Lovisa |
author_facet |
Ringstad, Lovisa |
author_sort |
Ringstad, Lovisa |
title |
Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition |
title_short |
Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition |
title_full |
Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition |
title_fullStr |
Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition |
title_full_unstemmed |
Interaction Between Antimicrobial Peptides and Phospholipid Membranes : Effects of Peptide Length and Composition |
title_sort |
interaction between antimicrobial peptides and phospholipid membranes : effects of peptide length and composition |
publisher |
Uppsala universitet, Institutionen för farmaci |
publishDate |
2009 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101989 http://nbn-resolving.de/urn:isbn:978-91-554-7540-6 |
work_keys_str_mv |
AT ringstadlovisa interactionbetweenantimicrobialpeptidesandphospholipidmembraneseffectsofpeptidelengthandcomposition |
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1716508454716178432 |