title: Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis.
abstract: Antibiotic therapy disrupts the human intestinal microbiota. In some patients rapid overgrowth of the enteric bacterium Klebsiella oxytoca results in antibiotic-associated hemorrhagic colitis (AAHC). We isolated and identified a toxin produced by K. oxytoca as the pyrrolobenzodiazepine tilivalline and demonstrated its causative action in the pathogenesis of colitis in an animal model. Tilivalline induced apoptosis in cultured human cells in vitro and disrupted epithelial barrier function, consistent with the mucosal damage associated with colitis observed in human AAHC and the corresponding animal model. Our findings reveal the presence of pyrrolobenzodiazepines in the intestinal microbiota and provide a mechanism for colitis caused by a resident pathobiont. The data link pyrrolobenzodiazepines to human disease and identify tilivalline as a target for diagnosis and neutralizing strategies in prevention and treatment of colitis.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria;
authors.forename: Georg
authors.initials: G
authors.lastname: Schneditz
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria;
authors.forename: Jana
authors.initials: J
authors.lastname: Rentner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria;
authors.forename: Sandro
authors.initials: S
authors.lastname: Roier
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria;
authors.forename: Jakob
authors.initials: J
authors.lastname: Pletz
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine and.
authors.forename: Kathrin A T
authors.initials: KA
authors.lastname: Herzog
authors.affiliation: Department of Gastroenterology, Infectiology and Rheumatology, Charité - Campus Benjamin Franklin, 10117 Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Bücker
authors.affiliation: Department of Gastroenterology, Infectiology and Rheumatology, Charité - Campus Benjamin Franklin, 10117 Berlin, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Troeger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria;
authors.forename: Stefan
authors.initials: S
authors.lastname: Schild
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria;
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Weber
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, 8010 Graz, Austria;
authors.forename: Rolf
authors.initials: R
authors.lastname: Breinbauer
authors.affiliation: Institute of Pathology, Medical University of Graz, 8036 Graz, Austria; and.
authors.forename: Gregor
authors.initials: G
authors.lastname: Gorkiewicz
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine and christoph.hoegenauer@medunigraz.at ellen.zechner@uni-graz.at.
authors.forename: Christoph
authors.initials: C
authors.lastname: Högenauer
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; christoph.hoegenauer@medunigraz.at ellen.zechner@uni-graz.at.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Zechner
mesh_terms: D039903:Actinobacteria / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology; D003603:Cytotoxins / Q000633:toxicity; D004768:Enterotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D006801:Humans; D041121:Klebsiella oxytoca / Q000235:genetics; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D005810:Multigene Family; D010406:Penicillins / Q000494:pharmacology; D010453:Peptide Synthases / Q000378:metabolism; D010455:Peptides / Q000633:toxicity*; D012270:Ribosomes
chemical_list: D000900:Anti-Bacterial Agents; D001570:Benzodiazepinones; D003603:Cytotoxins; D004768:Enterotoxins; D010406:Penicillins; D010455:Peptides; C093067:tilivalline; D053148:Caspase 3; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase
keywords: bacteria; cytotoxin; enteric microbiota