title: Immunomodulatory effects of Pseudomonas aeruginosa quorum sensing small molecule probes on mammalian macrophages.
abstract: Pseudomonas aeruginosa produces the quorum sensing signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). This natural product not only coordinates production of virulence factors by the bacterium, but also has immunomodulatory effects on the host organism. Immunomodulatory small molecules are valuable for immunology research and are potential therapeutics for autoimmune diseases such as rheumatoid arthritis, and immunosuppressive drugs following organ transplants. We describe the total synthesis of OdDHL using solid-supported reagents and scavengers, which has the potential to be used for automated analogue synthesis. OdDHL and four analogues were tested for their ability to activate or inhibit release of the pro-inflammatory mediators tumour necrosis factor alpha (TNFalpha) and nitric oxide (NO) from equine or murine macrophages (immune cells). Two of the analogues showed substantial immunomodulatory activity with these macrophages. One analogue showed differing species selectivity, being a potent antagonist in mouse cells, but a partial agonist in horse-derived macrophages. These compounds have the therapeutic potential to be used for protecting animals from bacterial septic shock.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UKCB2 1EW.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Thomas
authors.forename: Christine M
authors.initials: CM
authors.lastname: Böhner
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Williams
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Walsh
authors.forename: Mark
authors.initials: M
authors.lastname: Ladlow
authors.forename: Martin
authors.initials: M
authors.lastname: Welch
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001681:Biological Assay; D002460:Cell Line; D006736:Horses; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D010860:Pigments, Biological / Q000096:biosynthesis; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014774:Virulence / Q000276:immunology
chemical_list: D015335:Molecular Probes; D010860:Pigments, Biological; D014409:Tumor Necrosis Factor-alpha; C088386:homoserine lactone; D009569:Nitric Oxide; D015107:4-Butyrolactone