Omiganan interaction with bacterial membranes and cell wall models. Assigning a biological role to saturation.
Omiganan pentahydrochloride (ILRWPWWPWRRK-NH(2).5Cl) is an antimicrobial peptide currently in phase III clinical trials. This study aims to unravel the mechanism of action of this drug at the membrane level and address the eventual protective role of peptidoglycan in cell walls. The interaction of omiganan pentahydrochloride with bacterial and mammalian membrane models - large unilamellar vesicles of different POPC:POPG proportions - was characterized by UV-Vis fluorescence spectroscopy. The molar ratio partition constants obtained for the two anionic bacterial membrane models were very high ((18.9+/-1.3)x10(3) and (43.5+/-8.7)x10(3)) and about one order of magnitude greater than for the neutral mammalian models ((3.7+/-0.4)x10(3) for 100% POPC bilayers). At low lipid:peptide ratios there were significant deviations from the usual hyperbolic-like partition behavior of peptide vesicle titration curves, especially for the most anionic systems. Membrane saturation can account for such observations and mathematical models were derived to further characterize the peptide-lipid interaction under those conditions; a possible relation between saturation and MIC was deduced; this was supported by differential quenching studies of peptide internalization. Interaction with the bacterial cell wall was assessed using Staphylococcus aureus peptidoglycan extracts as a model. A strong partition towards the peptidoglycan mesh was observed, but not as large as for the membrane models.
Melo
Manuel Nuno
MN
Centro de Química e Bioquímica, Faculdade de Ciências da UL, Campo Grande, C8, 1749-016 Lisboa, Portugal.
Castanho
Miguel A R B
MA
D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013211:Staphylococcus aureus / Q000378:metabolism*
D023181:Antimicrobial Cationic Peptides; D010455:Peptides; D010457:Peptidoglycan; D010713:Phosphatidylcholines; D002784:Cholesterol; C478918:omiganan pentahydrochloride; C028694:1-palmitoyl-2-oleoylphosphatidylcholine