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 Schild & 2 Sonstige Christoph Högenauer, Ellen L. Zechner

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

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.

Originalspracheenglisch
Seiten (von - bis)3774-3783
Seitenumfang10
FachzeitschriftProceedings of the National Academy of Sciences of the United States of America
Jahrgang116
Ausgabenummer9
DOIs
PublikationsstatusVeröffentlicht - 26 Feb 2019

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Klebsiella oxytoca
Enterotoxins
Microtubules
Colitis
Intestines
DNA
Pseudomembranous Enterocolitis
Intestinal Diseases
Enterocytes
Microbiota
Mutagens
Tubulin
DNA Damage
Virulence
Cultured Cells
Apoptosis
Peptides
tilivalline

Schlagwörter

    ASJC Scopus subject areas

    • Allgemein

    Fields of Expertise

    • Human- & Biotechnology

    Dies zitieren

    Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities. / Unterhauser, Katrin; Pöltl, Lisa; Schneditz, Georg; Kienesberger, Sabine; Glabonjat, Ronald A.; Kitsera, Maksym; Pletz, Jakob; Josa-Prado, Fernando; Dornisch, Elisabeth; Lembacher-Fadum, Christian; Roier, Sandro; Gorkiewicz, Gregor; Lucena, Daniel; Barasoain, Isabel; Kroutil, Wolfgang; Wiedner, Marc; Loizou, Joanna I.; Breinbauer, Rolf; Díaz, José Fernando; Schild, Stefan; Högenauer, Christoph; Zechner, Ellen L.

    in: Proceedings of the National Academy of Sciences of the United States of America, Jahrgang 116, Nr. 9, 26.02.2019, S. 3774-3783.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Unterhauser, K, Pöltl, L, Schneditz, G, Kienesberger, S, Glabonjat, RA, Kitsera, M, Pletz, J, Josa-Prado, F, Dornisch, E, Lembacher-Fadum, C, Roier, S, Gorkiewicz, G, Lucena, D, Barasoain, I, Kroutil, W, Wiedner, M, Loizou, JI, Breinbauer, R, Díaz, JF, Schild, S, Högenauer, C & Zechner, EL 2019, 'Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities' Proceedings of the National Academy of Sciences of the United States of America, Jg. 116, Nr. 9, S. 3774-3783. https://doi.org/10.1073/pnas.1819154116
    Unterhauser, Katrin ; Pöltl, Lisa ; Schneditz, Georg ; Kienesberger, Sabine ; Glabonjat, Ronald A. ; Kitsera, Maksym ; Pletz, Jakob ; Josa-Prado, Fernando ; Dornisch, Elisabeth ; Lembacher-Fadum, Christian ; Roier, Sandro ; Gorkiewicz, Gregor ; Lucena, Daniel ; Barasoain, Isabel ; Kroutil, Wolfgang ; Wiedner, Marc ; Loizou, Joanna I. ; Breinbauer, Rolf ; Díaz, José Fernando ; Schild, Stefan ; Högenauer, Christoph ; Zechner, Ellen L. / Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities. in: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Jahrgang 116, Nr. 9. S. 3774-3783.
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    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.",
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    AU - Unterhauser, Katrin

    AU - Pöltl, Lisa

    AU - Schneditz, Georg

    AU - Kienesberger, Sabine

    AU - Glabonjat, Ronald A.

    AU - Kitsera, Maksym

    AU - Pletz, Jakob

    AU - Josa-Prado, Fernando

    AU - Dornisch, Elisabeth

    AU - Lembacher-Fadum, Christian

    AU - Roier, Sandro

    AU - Gorkiewicz, Gregor

    AU - Lucena, Daniel

    AU - Barasoain, Isabel

    AU - Kroutil, Wolfgang

    AU - Wiedner, Marc

    AU - Loizou, Joanna I.

    AU - Breinbauer, Rolf

    AU - Díaz, José Fernando

    AU - Schild, Stefan

    AU - Högenauer, Christoph

    AU - Zechner, Ellen L.

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    N2 - 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.

    AB - 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.

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