Combination of antimicrobial and endotoxin-neutralizing activities of novel oleoylamines

Abstract

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.

FIG. 1.

Scheme of the chemical synthesis of oleoylamines.

FIG. 2.

Neutralization of LPS-induced TNF-α release from human blood by 1 μM oleoylamines and 10 ng/ml LPS.

FIG. 3.

Correlation between experimental (Exp.) and calculated (Calc.) properties based on two descriptors. Top panel, MICs (E. coli) of compounds 1 to 7; bottom panel, ENCs for compounds 1 to 7. Equations for the line representing the best correlations shown in the top and bottom panels are as follows: log(1/MIC_{E. coli}) = 4.66 + 0.29 · NNmin + 0.0225 · ZX shadow and log(1/ENC₅₀) = −8.0 + 6.4 · YZ shadow + 6.18 · Balaban index, respectively.