Lipid Membrane Interactions of the Cationic Antimicrobial Peptide Chimeras Melimine and Cys-Melimine

Thomas Berry, Debarun Dutta, Renxun Chen, Andrea Leong, Huixin Wang, William A Donald, Maryam Parviz, Bruce Cornell, Mark Willcox, Naresh Kumar, Charles G Cranfield

Research output: Contribution to journalArticlepeer-review


Melimine and its derivatives are synthetic chimeric antimicrobial agents based on protamine and melittin. The binding of solubilized melimine and its derivative, with a cysteine on N-terminus, (cys-melimine) on tethered bilayer lipid membranes (tBLMs) was examined using ac electrical impedance spectroscopy. The addition of melimine and cys-melimine initially increased membrane conduction, which subsequently falls over time. The results were obtained for tBLMs comprising zwitterionic phosphatidylcholine, anionic phosphatidylglycerol, or tBLMs made using purified lipids from Escherichia coli. The effect on conduction is more marked with the cysteine variant than the noncysteine variant. The variation in membrane conduction most probably arises from individual melimines inducing increased ionic permeability, which is then reduced as the melimines aggregate and phase-separate within the membrane. The actions of these antimicrobials are modeled in terms of altering the critical packing parameter (CPP) of the membranes. The variations in the peptide length of cys-melimine were compared with a truncated version of the peptide, cys-mel4. The results suggest that the smaller molecule impacts the membrane by a mechanism that increases the average CPP, reducing membrane conduction. Alternatively, an uncharged alanine-replacement version of melimine still produced an increase in membrane conduction, further supporting the CPP model of geometry-induced toroidal pore alterations. All the data were then compared to their antimicrobial effectiveness for the Gram-positive and Gram-negative strains of bacteria, and their fusogenic properties were examined using dynamic light scattering in 1-oleoyl-2-hydroxy- sn-glycero-3-phosphocholine lipid spheroids. We conclude that a degree of correlation exists between the antimicrobial effectiveness of the peptides studied here and their modulation of membrane conductivity.

Original languageEnglish
Pages (from-to)11586-11592
Number of pages7
Issue number38
Early online date17 Aug 2018
Publication statusPublished - 25 Sept 2018


  • Amino Acid Sequence
  • Anti-Bacterial Agents/chemistry
  • Antimicrobial Cationic Peptides/chemistry
  • Cysteine/analogs & derivatives
  • Escherichia coli/drug effects
  • Lipid Bilayers/chemistry
  • Microbial Sensitivity Tests
  • Permeability/drug effects
  • Pseudomonas aeruginosa/drug effects
  • Staphylococcus aureus/drug effects
  • Staphylococcus epidermidis/drug effects


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