Gram‐Negative Extremophile Lipopolysaccharides: Promising Source of Inspiration for a New Generation of Endotoxin Antagonists

Lorenzo, Flaviana Di; Billod, Jean-Marc; Martín‐Santamaría, Sonsoles; Silipo, Alba; Molinaro, Antonio

doi:10.1002/ejoc.201700113

Cited by 29 publications

(46 citation statements)

References 179 publications

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“…Indeed, it was previously reported that LPSs from non-pathogenic bacteria can act as TLR4/MD-2 antagonists or partial antagonists towards toxic LPSs [ 12 ]. As a consequence, there is a constant search for LPS antagonist candidates inspired by a natural source: namely LPS analogues able to bind the receptorial complex, thus competing with toxic LPSs, but not capable of triggering an effective immune response [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Deep-Sea Polyextremophile Halobacteroides lacunaris TB21 Rough-Type LPS: Structure and Inhibitory Activity towards Toxic LPS

et al. 2017

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The structural characterization of the lipopolysaccharide (LPS) from extremophiles has important implications in several biomedical and therapeutic applications. The polyextremophile Gram-negative bacterium Halobacteroides lacunaris TB21, isolated from one of the most extreme habitats on our planet, the deep-sea hypersaline anoxic basin Thetis, represents a fascinating microorganism to investigate in terms of its LPS component. Here we report the elucidation of the full structure of the R-type LPS isolated from H. lacunaris TB21 that was attained through a multi-technique approach comprising chemical analyses, NMR spectroscopy, and Matrix-Assisted Laser Desorption Ionization (MALDI) mass spectrometry. Furthermore, cellular immunology studies were executed on the pure R-LPS revealing a very interesting effect on human innate immunity as an inhibitor of the toxic Escherichia coli LPS.

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Section: Introductionmentioning

confidence: 99%

The Deep-Sea Polyextremophile Halobacteroides lacunaris TB21 Rough-Type LPS: Structure and Inhibitory Activity towards Toxic LPS

et al. 2017

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“…HEX 311 lipid A (Scheme ) is mainly composed of tetra‐ and triacylated species, that is, a highly hypoacylated species, which might be poorly recognized by the sponge immune system. Moreover, if hexaacylated forms occur, these present a 3+3 distribution of the acyl chains, which are also typically correlated to a weak immunopotential . Therefore, the expression of lipid A with structural features leading to weak immunoactivity might be a key requirement to establish the successful symbiosis between the microbe and sponge.…”

Section: Resultsmentioning

confidence: 99%

The Lipid A Structure from the Marine Sponge Symbiont Endozoicomonas sp. HEX 311

et al. 2018

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Endozoicomonas sp. HEX311 is a Gram-negative bacterium known to establish a commensal interaction with the marine demosponge Suberites domuncula. The molecular bases of the sponge-microbe interaction events are still poorly defined. Nevertheless, it has been proved that S. domuncula possesses an innate immune system with similarities to the mammalian one and is able to recognize the main component of the Gram-negative bacteria cell wall: the lipopolysaccharide. Whether this recognition occurs in a structure-dependent manner, which is typical for mammalian immune system receptors, is still under investigation. Herein, we report the Endozoicomonas sp. HEX311 lipid A structure obtained by a combination of data attained from chemical, MALDI MS, and MS approaches. The lipid A is a complex family of species decorated by pyrophosphate and phosphate units and carrying (R)-3-hydroxydodecanoic acid, (R)-3-hydroxytetradecanonic acid, iso-2-hydroxyundecanoic acid, iso-(R)-3-hydroxyundecanoic acid, and iso-nonanoic acid as acyl chains.

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“…In some natural lipid A variants, phosphates in positions C1 and C4′ are covalently functionalized with phosphate, ethanolamine, ethanolamine phosphate, ethanolamine di-phosphate ( C. jejuni ), and sugars as glycosylamine, 4-amino-4-deoxy- l -arabinopyranose and d -arabinofuranose [ 41 ].…”

Section: Structure-activity Relationship In Natural and Synthetic mentioning

confidence: 99%

“…The elucidation of new lipid A chemical structures deriving from bacteria species is a field in continuous evolution, and SAR in new lipid A types will provide important information for designing new synthetic TLR4 modulators [ 41 , 52 ].…”

Section: Structure-activity Relationship In Natural and Synthetic mentioning

confidence: 99%

The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling

Cochet

Peri

2017

IJMS

135

102

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The interactions between sugar-containing molecules from the bacteria cell wall and pattern recognition receptors (PRR) on the plasma membrane or cytosol of specialized host cells are the first molecular events required for the activation of higher animal’s immune response and inflammation. This review focuses on the role of carbohydrates of bacterial endotoxin (lipopolysaccharide, LPS, lipooligosaccharide, LOS, and lipid A), in the interaction with the host Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. The lipid chains and the phosphorylated disaccharide core of lipid A moiety are responsible for the TLR4 agonist action of LPS, and the specific interaction between MD-2, TLR4, and lipid A are key to the formation of the activated complex (TLR4/MD-2/LPS)2, which starts intracellular signalling leading to nuclear factors activation and to production of inflammatory cytokines. Subtle chemical variations in the lipid and sugar parts of lipid A cause dramatic changes in endotoxin activity and are also responsible for the switch from TLR4 agonism to antagonism. While the lipid A pharmacophore has been studied in detail and its structure-activity relationship is known, the contribution of core saccharides 3-deoxy-d-manno-octulosonic acid (Kdo) and heptosyl-2-keto-3-deoxy-octulosonate (Hep) to TLR4/MD-2 binding and activation by LPS and LOS has been investigated less extensively. This review focuses on the role of lipid A, but also of Kdo and Hep sugars in LPS/TLR4 signalling.

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Gram‐Negative Extremophile Lipopolysaccharides: Promising Source of Inspiration for a New Generation of Endotoxin Antagonists

Cited by 29 publications

References 179 publications

The Deep-Sea Polyextremophile Halobacteroides lacunaris TB21 Rough-Type LPS: Structure and Inhibitory Activity towards Toxic LPS

The Deep-Sea Polyextremophile Halobacteroides lacunaris TB21 Rough-Type LPS: Structure and Inhibitory Activity towards Toxic LPS

The Lipid A Structure from the Marine Sponge Symbiont Endozoicomonas sp. HEX 311

The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling

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