title: Antimicrobial activity and membrane selective interactions of a synthetic lipopeptide MSI-843.
abstract: Lipopeptide MSI-843 consisting of the nonstandard amino acid ornithine (Oct-OOLLOOLOOL-NH2) was designed with an objective towards generating non-lytic short antimicrobial peptides, which can have significant pharmaceutical applications. Octanoic acid was coupled to the N-terminus of the peptide to increase the overall hydrophobicity of the peptide. MSI-843 shows activity against bacteria and fungi at micromolar concentrations. It permeabilizes the outer membrane of Gram-negative bacterium and a model membrane mimicking bacterial inner membrane. Circular dichroism investigations demonstrate that the peptide adopts alpha-helical conformation upon binding to lipid membranes. Isothermal titration calorimetry studies suggest that the peptide binding to membranes results in exothermic heat of reaction, which arises from helix formation and membrane insertion of the peptide. 2H NMR of deuterated-POPC multilamellar vesicles shows the peptide-induced disorder in the hydrophobic core of bilayers. 31P NMR data indicate changes in the lipid head group orientation of POPC, POPG and Escherichia colitotal lipid bilayers upon peptide binding. Results from 31P NMR and dye leakage experiments suggest that the peptide selectively interacts with anionic bilayers at low concentrations (up to 5 mol%). Differential scanning calorimetry experiments on DiPOPE bilayers and 31P NMR data from E.coli total lipid multilamellar vesicles indicate that MSI-843 increases the fluid lamellar to inverted hexagonal phase transition temperature of bilayers by inducing positive curvature strain. Combination of all these data suggests the formation of a lipid-peptide complex resulting in a transient pore as a plausible mechanism for the membrane permeabilization and antimicrobial activity of the lipopeptide MSI-843.
authors.affiliation: Biophysics Research Division and Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Sathiah
authors.initials: S
authors.lastname: Thennarasu
authors.forename: Dong-Kuk
authors.initials: DK
authors.lastname: Lee
authors.forename: Anmin
authors.initials: A
authors.lastname: Tan
authors.forename: U
authors.initials: U
authors.lastname: Prasad Kari
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002151:Calorimetry; D002462:Cell Membrane / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002942:Circular Dichroism; D004926:Escherichia coli / Q000187:drug effects; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009952:Ornithine / Q000737:chemistry; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013696:Temperature
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D009952:Ornithine