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

Autor:	Unterhauser K; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Pöltl L; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Schneditz G; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Kienesberger S; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Glabonjat RA; Institute of Chemistry, University of Graz, A-8010 Graz, Austria., Kitsera M; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Pletz J; Institute of Chemistry, University of Graz, A-8010 Graz, Austria.; Institute of Organic Chemistry, Graz University of Technology, A-8010 Graz, Austria., Josa-Prado F; Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Scientíficas (CIB-CSIC), 28040 Madrid, Spain., Dornisch E; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Lembacher-Fadum C; Institute of Organic Chemistry, Graz University of Technology, A-8010 Graz, Austria., Roier S; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria., Gorkiewicz G; BioTechMed-Graz, A-8010 Graz, Austria.; Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria., Lucena D; Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Scientíficas (CIB-CSIC), 28040 Madrid, Spain., Barasoain I; Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Scientíficas (CIB-CSIC), 28040 Madrid, Spain., Kroutil W; Institute of Chemistry, University of Graz, A-8010 Graz, Austria., Wiedner M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, A-1090 Vienna, Austria., Loizou JI; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, A-1090 Vienna, Austria., Breinbauer R; Institute of Organic Chemistry, Graz University of Technology, A-8010 Graz, Austria.; BioTechMed-Graz, A-8010 Graz, Austria., Díaz JF; Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Scientíficas (CIB-CSIC), 28040 Madrid, Spain., Schild S; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.; BioTechMed-Graz, A-8010 Graz, Austria., Högenauer C; BioTechMed-Graz, A-8010 Graz, Austria.; Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria., Zechner EL; Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria; ellen.zechner@uni-graz.at.; BioTechMed-Graz, A-8010 Graz, Austria.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Feb 26; Vol. 116 (9), pp. 3774-3783. Date of Electronic Publication: 2019 Feb 11.
DOI:	10.1073/pnas.1819154116
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest. (Copyright © 2019 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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