Exposing the true bactericidal potency of cyclotides: explained by lipid selectivity, structural characteristics and correlating antimicrobial activities
(English)Manuscript (preprint) (Other academic)
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 activity against eukaryotic cells and enveloped viruses. In the current study, we show that potent antibacterial activity is frequent among cyclotides as long as the activity inhibiting presence of rich growth media is avoided. For that purpose a modified microdilution assay protocol was developed. This, the largest and most diverse set of cyclotides to be tested for antibacterial and antifungal activity, show that most cyclotides are active in this respect, especially against Gram-negative bacteria. Activity was observed at sub-micromolar concentrations for three of the cyclotides surpassing that of the potent control peptides melittin and LL-37. Noteworthy, two net anionic cyclotides were active on Pseudomonas aeruginosa at low micromolar concentrations. Activity against Staphylococcus aureus or Candida albicans was lower and less frequent. Permeabilizing activity on liposomes of various compositions was compared with effects on bacteria, Candida and lymphoma cells to which physiochemical properties of the cyclotides could be assigned. Analysis of quantitative structure-activity relationship found correlations between molecular patterns, phospholipid specificity and antimicrobial activity. Although certain bracelet cyclotides, with broad-spectrum activity, relied more on electrostatic and hydrophobic parameters for their bioactivity, those with primarily Gram-negative activity, in particular against P. aeruginosa, were achieving membrane binding and disruption in a phospholipid specific manner, namely a high affinity for phosphatidylethanolamine (PE). We conclude that the high PE-selectivity is linked to the potency of antibacterial activity.
cyclotide; membrane; phosphatidylethanolamine; cytotoxicity; antibacterial; antifungal; peptide surface chemistry
Research subject Pharmacognosy; Physical Chemistry
IdentifiersURN: urn:nbn:se:uu:diva-292756OAI: oai:DiVA.org:uu-292756DiVA: diva2:926606