title: Phospholipid-driven differences determine the action of the synthetic antimicrobial peptide OP-145 on Gram-positive bacterial and mammalian membrane model systems.
abstract: OP-145, a synthetic antimicrobial peptide developed from a screen of the human cathelicidin LL-37, displays strong antibacterial activities and is--at considerably higher concentrations--lytic to human cells. To obtain more insight into its actions, we investigated the interactions between OP-145 and liposomes composed of phosphatidylglycerol (PG) and phosphatidylcholine (PC), resembling bacterial and mammalian membranes, respectively. Circular dichroism analyses of OP-145 demonstrated a predominant α-helical conformation in the presence of both membrane mimics, indicating that the different membrane-perturbation mechanisms are not due to different secondary structures. Membrane thinning and formation of quasi-interdigitated lipid-peptide structures was observed in PG bilayers, while OP-145 led to disintegration of PC liposomes into disk-like micelles and bilayer sheets. Although OP-145 was capable of binding lipoteichoic acid and peptidoglycan, the presence of these bacterial cell wall components did not retain OP-145 and hence did not interfere with the activity of the peptide toward PG membranes. Furthermore, physiological Ca++ concentrations did neither influence the membrane activity of OP-145 in model systems nor the killing of Staphylococcus aureus. However, addition of OP-145 at physiological Ca++-concentrations to PG membranes, but not PC membranes, resulted in the formation of elongated enrolled structures similar to cochleate-like structures. In summary, phospholipid-driven differences in incorporation of OP-145 into the lipid bilayers govern the membrane activity of the peptide on bacterial and mammalian membrane mimics.
authors.affiliation: Institute of Molecular Biosciences, Biophysics Division, University of Graz, NAWI Graz, Graz, Austria; BioTechMed-Graz, Austria. Electronic address: nermina.malanovic@uni-graz.at.
authors.forename: Nermina
authors.initials: N
authors.lastname: Malanovic
authors.affiliation: Institute of Molecular Biosciences, Biophysics Division, University of Graz, NAWI Graz, Graz, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Leber
authors.affiliation: BioTechMed-Graz, Austria; Institute of Environmental Biotechnology, Graz University of Technology, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Schmuck
authors.affiliation: Institute of Inorganic Chemistry, Graz University of Technology, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kriechbaum
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cordfunke
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: de Breij
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nibbering
authors.affiliation: Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria; Core Facility Ultrastructure Analysis, Center for Medical Research, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Institute of Molecular Biosciences, Biophysics Division, University of Graz, NAWI Graz, Graz, Austria; BioTechMed-Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Lohner
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D010743:Phospholipids
keywords: Antibacterial activity; Cytotoxicity; Lipoteichoic acid; Membrane biophysics; Membrane mimics; Peptidoglycan