Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

Katrin Unterhauser, Lisa Pöltl, Georg Schneditz, Sabine Kienesberger, Ronald A. Glabonjat, Maksym Kitsera, Jakob Pletz, Fernando Josa-Prado, Elisabeth Dornisch, Christian Lembacher-Fadum, Sandro Roier, Gregor Gorkiewicz, Daniel Lucena, Isabel Barasoain, Wolfgang Kroutil, Marc Wiedner, Joanna I. Loizou, Rolf Breinbauer, José Fernando Díaz, Stefan SchildChristoph Högenauer, Ellen L. Zechner*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca. Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells—a hallmark feature of AAHC—by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.

Original languageEnglish
Pages (from-to)3774-3783
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number9
DOIs
Publication statusPublished - 26 Feb 2019

Keywords

  • Antibiotic-induced diarrhea
  • DNA damage
  • Dysbiosis
  • Intestinal microbiota
  • Tubulin inhibitor
  • Klebsiella Infections/genetics
  • Enterotoxins/biosynthesis
  • Humans
  • Intestines/microbiology
  • Peptides/metabolism
  • Epithelial Cells/microbiology
  • Microtubules/drug effects
  • Animals
  • Host Microbial Interactions/genetics
  • Enterocolitis, Pseudomembranous/genetics
  • Benzodiazepinones/metabolism
  • DNA Damage/drug effects
  • Mice
  • Klebsiella oxytoca/genetics
  • Oxyquinoline/analogs & derivatives

ASJC Scopus subject areas

  • General

Fields of Expertise

  • Human- & Biotechnology

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