uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Oligotryptophan-tagged antimicrobial peptides and the role of the cationic sequence
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Pharmaceutical Physical Chemistry)ORCID iD: 0000-0001-9070-6944
Department of Clinical Sciences, Lund University. (Dermatology and Venereology)
Department of Clinical Sciences, Lund University. (Dermatology and Venereology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Pharmaceutical Physical Chemistry)
2009 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1788, no 9, 1916-1923 p.Article in journal (Refereed) Published
Abstract [en]

The effects of varying the cationic sequence of oligotryptophan-tagged antimicrobial peptides were investigated in terms of peptide adsorption to model lipid membranes, liposome leakage induction, and antibacterial potency. Heptamers of lysine (K7) and arginine (R7) were lytic against Escherichia coli bacteria at low ionic strength. In parallel, both peptides adsorbed on to bilayers formed by E. coli phospholipids, and caused leakage in the corresponding liposomes. K7 was the more potent of the two peptides in causing liposome leakage, although the adsorption of this peptide on E. coli membranes was lower than that of R7. The bactericidal effect, liposome lysis, and membrane adsorption were all substantially reduced at physiological ionic strength. When a tryptophan pentamer tag was linked to the C-terminal end of these peptides, substantial peptide adsorption, membrane lysis, and bacterial killing was observed also at high ionic strength, and also for a peptide of lower cationic charge density (KNKGKKN-W5). Strikingly, the order of membrane lytic potential of the cationic peptides investigated was reversed when tagged. This and other aspects of peptide behavior and adsorption, in conjunction with effects on liposomes and bacteria, suggest that tagged and untagged peptides act by different lytic mechanisms, which to some extent counterbalance each other. Thus, while the untagged peptides act by generating negative curvature strain in the phospholipid membrane, the tagged peptides cause positive curvature strain. The tagged heptamer of arginine, R7W5, was the best candidate for E. coli membrane lysis at physiological salt conditions and proved to be an efficient antibacterial agent.

Place, publisher, year, edition, pages
2009. Vol. 1788, no 9, 1916-1923 p.
Keyword [en]
antimicrobial, peptide, adsorption, oligotryptophan, oligolysine, oligoarginine, membrane, liposomes, phospholipid, bilayer
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-100980DOI: 10.1016/j.bbamem.2009.06.001ISI: 000269859400025PubMedID: 19505433OAI: oai:DiVA.org:uu-100980DiVA: diva2:211461
Available from: 2009-04-15 Created: 2009-04-15 Last updated: 2017-12-13
In thesis
1. Antimicrobial Peptide Interactions with Phospholipid Membranes: Effects of Peptide and Lipid Composition on Membrane Adsorption and Disruption
Open this publication in new window or tab >>Antimicrobial Peptide Interactions with Phospholipid Membranes: Effects of Peptide and Lipid Composition on Membrane Adsorption and Disruption
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The interactions between antimicrobial peptides and phospholipid membranes were investigated, in terms of lipid headgroup variations and the role of cholesterol, as well as peptide composition and structure. Also strategies for increasing proteolytic stability were evaluated. The interactions were studied on model membranes in the form of liposomes and supported bilayers, through a combination of ellipsometry, fluorescence spectroscopy, circular dichroism, dynamic light scattering, electrophoresis, electron cryomicroscopy, and bacterial/cell culture experiments.

The findings showed that membrane tolerance against the lytic activity of melittin, was increased on anionic membranes by electrostatic arrest in the headgroup region, and was reduced by hydration repulsion. The presence of cholesterol caused a reduction in melittin adsorption, while at the same time reducing membrane tolerance per adsorbed peptide. Differences in membrane leakage mechanisms were also attributed to cholesterol, where large scale structural effects contributed to the leakage, while other membranes followed the pore formation model.

Substituting specific amino acids for tryptophan on an LL-37 derivative, was shown to increase stability against bacterial proteases, while at the same time significantly increasing antibacterial properties. These substitutions, as well as terminal modifications, increased adsorption and membrane lytic properties in a way that was less dependent on electrostatics. Furthermore, by comparing short cationic peptides with oligotryptophan end-tagged versions, the lytic mechanism of end-tagged peptides, and the different contributions of arginine and lysine to membrane adsorption and disruption were demonstrated.

This thesis is a contribution to the development of antimicrobial peptides as therapeutic alternatives to conventional antibiotics.

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 ; 97
Keyword
antimicrobial, peptide, adsorption, liposome, membrane, melittin, cholesterol, tryptophan, phospholipid, bilayer
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-100966 (URN)978-91-554-7520-8 (ISBN)
Public defence
2009-05-20, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-29 Created: 2009-04-15 Last updated: 2009-05-12Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Strömstedt, Adam A.
By organisation
Department of Pharmacy
In the same journal
Biochimica et Biophysica Acta - Biomembranes
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 499 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf