A novel lipid A from Halomonas magadiensis inhibits enteric LPS‐induced human monocyte activation

Abstract

Lipopolysaccharide (LPS) endotoxin is the bacterial product responsible for the clinical syndrome of Gram‐negative septicemia and endotoxic shock. During sepsis, microbial antigens, such as LPS, activate monocytes and macrophages to produce several pro‐inflammatory cytokines, among which tumor necrosis factor‐α (TNF‐α) appears to be very important for the development of endotoxic shock. The endotoxic properties of LPS principally reside in the lipid A (LIP A) component, which is the primary immunostimulatory center of Gram‐negative bacteria. In recent years there has been a continuous effort to identify molecules able to antagonize the deleterious effects of endotoxic shock. In this study we show that a novel LIP A fraction from the LPS of Halomonas magadiensis (Hm), a Gram‐negative extremophilic and alkaliphilic bacterium, significantly inhibits the synthesis of TNF‐α by human monocytes activated by Escherichia coli LPS. LIP A from Hm exerts these effects by interfering with E. coli LPS for activation of Toll‐like receptor 4 expressed in human cells. This result defines Hm LIP A as a novel class of LPS antagonist whose structural features could be utilized for the design of compounds for the treatment of Gram‐negative sepsis.

Studies towards lipid A: a synthetic strategy for the enantioselective preparation of 3-hydroxy fatty acids

“…This reagent produced the asymmetric carbon atom HO with the required (R)-stereochemistry. The enantiomeric excess (90%) was determined by 1 H NMR spectroscopy of the corresponding 1-methoxy derivative using the chiral shift reagent Eu(hfc) 3 in comparison with a racemic mixture. 7 Concerning the conversion of diol (R)-(À)-3 into the cyanoalcohol (R)-(À)-4, we believed that it could be available through the regioselective opening of the chiral epoxide 5 that can be produced, as reported, 8 by using a betaine-like intermediate.…”

“…Since lipid A from H. magadiensis interferes with cytokine induction in human cells, 3 it would be very interesting to observe the biological activity of each component of this lipid A as a potential antagonist. We are currently developing a flexible procedure for the facile synthesis of its constituents and, within this context, an efficient preparation of lipidic moieties with high enantiomeric excess is also required.…”

A Cyanobacterial Lipopolysaccharide Antagonist Inhibits Cytokine Production Induced byNeisseria meningitidisin a Human Whole-Blood Model of Septicemia

“…Many studies have described different lipid A analogues and chemically modified LPS derivatives (10,11,19,27,34) as well as LPS-neutralizing molecules (1,4,17) as potential inhibitors of inflammatory responses induced by Ec-LPS. To date, only LPS-like molecules isolated from the bacteria Rhodobacter capsulatus, Helicobacter pylori, Porphyromonas gingivalis, Capnocytophaga ochracea, and Oscillatoria planktothrix FP1 have been reported to act as LPS receptor antagonists (24,26,28,42).…”

Structural characterization of the lipid A from the LPS of the haloalkaliphilic bacterium Halomonas pantelleriensis

“…The biological activity of lipid A strongly depends on its primary structure, especially the fatty acid composition and distribution (Holst et al 1996;Seydel et al 2000). As the lipid A of H. magadiensis displayed a strong antagonist activity (Ialenti et al 2006), it will be very interesting to observe the biological activity of the lipid A from H. pantelleriensis strain to check if there are any structure-activity relationships. To test the biological activity of H. pantelleriensis lipid A, immunological assays on human monocytic cell line THP-1 were performed.…”