title: In Vitro Evaluation of the Interaction of Dextrin-Colistin Conjugates with Bacterial Lipopolysaccharide.
abstract: Dextrin-colistin conjugates have been developed with the aim of achieving reduced clinical toxicity associated with colistin, also known as polymyxin E, and improved targeting to sites of bacterial infection. This study investigated the in vitro ability of such dextrin-colistin conjugates to bind and modulate bacterial lipopolysaccharide (LPS), and how this binding affects its biological activity. These results showed that colistin and amylase-activated dextrin-colistin conjugate to a lesser extent induced aggregation of LPS to form a stacked bilayer structure with characteristic dimensions, although this did not cause any substantial change in its secondary structure. In biological studies, both colistin and dextrin-colistin conjugate effectively inhibited LPS-induced hemolysis and tumor necrosis factor α (TNFα) secretion in a concentration-dependent manner, but only dextrin-colistin conjugate showed no additive toxicity at higher concentrations. This study provides the first direct structural experimental evidence for the binding of dextrin-colistin conjugates and LPS and gives insight into the mode of action of dextrin-colistin conjugates.
authors.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University , Heath Park, Cardiff CF14 4XY, U.K.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: Department of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich , Medway Campus, Central Avenue, Chatham Maritime ME4 4TB, U.K.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Cattoz
authors.affiliation: Institut Laue-Langevin , DS/LSS group, 6, rue Jules Horowitz, 38042 Cedex 9 Grenoble, France.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schweins
authors.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University , Heath Park, Cardiff CF14 4XY, U.K.
authors.forename: Konrad
authors.initials: K
authors.lastname: Beck
authors.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University , Heath Park, Cardiff CF14 4XY, U.K.
authors.forename: David W
authors.initials: DW
authors.lastname: Thomas
authors.affiliation: Department of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich , Medway Campus, Central Avenue, Chatham Maritime ME4 4TB, U.K.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Griffiths
authors.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University , Heath Park, Cardiff CF14 4XY, U.K.
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Ferguson
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000737:chemistry*; D002460:Cell Line; D003091:Colistin / Q000737:chemistry* / Q000494:pharmacology*; D003912:Dextrins / Q000737:chemistry* / Q000494:pharmacology*; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008033:Limulus Test; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000737:chemistry*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D003912:Dextrins; D004731:Endotoxins; D008070:Lipopolysaccharides; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000681:Amylases; D003091:Colistin