Combination of antimicrobial and endotoxin-neutralizing activities of novel oleoylamines.
A combination of antimicrobial and endotoxin-neutralizing activities is desired in order to prevent progression from infection to sepsis due to the release of lipopolysaccharide from dying gram-negative bacteria. Lipopolyamines have emerged as a new type of endotoxin-neutralizing compound, but their antimicrobial activity has not been investigated. We synthesized a series of 10 oleoylamines differing in the polyamino head group, particularly in the number and separation between nitrogen atoms and the position of the oleoyl moiety. Compounds showed activity against both gram-negative and gram-positive bacteria in the micromolar range. Compounds were able to provide penetration of ethidium bromide into bacteria, indicating effects on the bacterial membrane. Oleoylamines neutralized endotoxin in Limulus amoebocyte lysate assays and by neutralization of tumor necrosis factor alpha release in human blood. Comparison of biological activities of compounds identified structural properties responsible for antimicrobial activity, and quantitative structure-property relationship analysis provided a quantitative model for prediction of activity of oleoylamines.
Zorko
Mateja
M
Laboratory of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
Majerle
Andreja
A
Sarlah
David
D
Keber
Mateja Mancek
MM
Mohar
Barbara
B
Jerala
Roman
R
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006461:Hemolysis; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
C118665:1,3-dioleoyloxy-2-(6-carboxyspermyl)propylamide; D000900:Anti-Bacterial Agents; D004731:Endotoxins; D005229:Fatty Acids, Monounsaturated; D008070:Lipopolysaccharides