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: Georg Schneditz, Jana Rentner, Sandro Roier, Jakob Pletz, Kathrin A T Herzog, Roland Bücker, Hanno Troeger, Stefan Schild, Hansjörg Weber, Rolf Breinbauer, Gregor Gorkiewicz, Christoph Högenauer, Ellen L Zechner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 36 Pg. 13181-6 (Sep 09 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25157164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Benzodiazepinones
• Cytotoxins
• Enterotoxins
• Penicillins
• Peptides
• tilivalline
• Caspase 3
• Peptide Synthases
• non-ribosomal peptide synthase

Topics

• Actinobacteria (metabolism)
• Animals
• Anti-Bacterial Agents (adverse effects)
• Apoptosis (drug effects)
• Benzodiazepinones (toxicity)
• Caspase 3 (metabolism)
• Colitis (chemically induced, pathology)
• Cytotoxins (toxicity)
• Enterotoxins (toxicity)
• Epithelial Cells (drug effects, microbiology, pathology)
• Humans
• Klebsiella oxytoca (genetics)
• Mice, Inbred C57BL
• Molecular Sequence Data
• Multigene Family
• Penicillins (pharmacology)
• Peptide Synthases (metabolism)
• Peptides (toxicity)
• Ribosomes