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Bactericidal activity of cyclotides where phosphatidylethanolamine-lipid selectivity determines antimicrobial spectra
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.ORCID iD: 0000-0001-9070-6944
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
2017 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1859, no 10, 1986-2000 p.Article in journal (Refereed) Published
Abstract [en]

Cyclotides are a family of plant peptides characterized by a cystine knot embedded in a macrocyclic backbone. They bind to and disrupt phospholipid membranes, which explain their lytic activity on cells. In this study, we expose the full antibacterial potency of cyclotides by avoiding its inhibition by rich growth media assay conditions. For that purpose a two-step microdilution assay protocol was developed, using non-growing conditions during initial peptide incubation. A diverse set of cyclotides was tested for antibacterial and antifungal activity, and the results show that most cyclotides are active under these conditions, especially against Gram-negative bacteria. Activity was observed at sub-micromolar concentrations for three of the cyclotides tested, surpassing that of the control peptides LL-37 and melittin. Noteworthy, two anionic cyclotides were active on Pseudomonas aeruginosa at low micromolar concentrations. Broad-spectrum activity was pronounced among cycloviolacin cyclotides, which included activity on Staphylococcus aureus and Candida albicans. The factors influencing their bactericidal spectrum were revealed by correlating antimicrobial activity with membrane permeabilization on various liposome systems and with the physiochemical properties of the cyclotides. Whereas general electrostatic and hydrophobic parameters are more important for broad-spectrum cyclotides; a phospholipid-specific mechanism of membrane permeabilization, through interaction with phosphatidylethanolamine-lipids, is essential for cyclotides active primarily on Gram-negative bacteria.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2017. Vol. 1859, no 10, 1986-2000 p.
Keyword [en]
Cyclotide, Antimicrobial peptide, Antibacterial, Membrane permeabilization, Phosphatidylethanolamine-binding, Structure-activity relationship
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-336446DOI: 10.1016/j.bbamem.2017.06.018ISI: 000411419000024PubMedID: 28669767OAI: oai:DiVA.org:uu-336446DiVA: diva2:1165886
Funder
Swedish Society of Medicine, SLS-254511Swedish Research Council, 2012-5063
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2017-12-14Bibliographically approved

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Strömstedt, Adam A.Göransson, Ulf

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