Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1859, Issue 10, Pages 1986-2000Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2017.06.018
Keywords
Cyclotide; Antimicrobial peptide; Antibacterial; Membrane permeabilization; Phosphatidylethanolamine-binding; Structure-activity relationship
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Funding
- Swedish Society of Medicine [SLS-254511]
- Swedish Research Council [2012-5063]
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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. (C) 2017 Elsevier B.V. All rights reserved.
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