Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities.
Katrin UnterhauserLisa PöltlGeorg SchneditzSabine KienesbergerRonald A GlabonjatMaksym KitseraJakob PletzFernando Josa-PradoElisabeth DornischChristian Lembacher-FadumSandro RoierGregor GorkiewiczDaniel LucenaIsabel BarasoainWolfgang KroutilMarc WiednerJoanna I LoizouRolf BreinbauerJosé Fernando DíazStefan SchildChristoph HögenauerEllen L ZechnerPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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.
Keyphrases
- endothelial cells
- circulating tumor
- single molecule
- ms ms
- induced pluripotent stem cells
- cell cycle arrest
- oxidative stress
- cell free
- healthcare
- pluripotent stem cells
- magnetic resonance
- cell death
- endoplasmic reticulum stress
- machine learning
- type diabetes
- ulcerative colitis
- computed tomography
- insulin resistance
- deep learning
- cystic fibrosis
- signaling pathway
- pseudomonas aeruginosa
- risk factors
- biofilm formation
- cell proliferation
- circulating tumor cells