Synthesis and Isotopic Labelling of Tilimycin and Tilivalline, Cytotoxic Secondary Metabolites of Klebsiella Oxytoca

Christian Lembacher-Fadum (Speaker), Elisabeth Dornisch (Contributor), Jakob Pletz (Contributor), Maksym Kitsera (Contributor), Ronald A. Glabonjat (Contributor), Katrin Unterhauser (Contributor), Christoph Högenauer (Contributor), Kevin A. Francesconi (Contributor), Wolfgang Kroutil (Contributor), Klaus Zangger (Contributor), Ellen L. Zechner (Contributor), Breinbauer, R. (Contributor)

Activity: Talk or presentationTalk at conference or symposiumScience to science

Description

In some cases, antibiotic therapy can lead to antibiotic-associated hemorrhagic colitis (AAHC), which is caused by rapid overgrowth of the enteric bacterium Klebsiella oxytoca. The pyrrolobenzodiazepine tilivalline was the first identified metabolite of K. oxytoca, which is secreted into the intestinal lumen causing epithelial apoptosis and leading to AAHC. However, the unexpected cytotoxic activity of a non-tilivalline-producing mutant strain on HeLa cells suggested that K. oxytoca might be able to produce another, even more cytotoxic metabolite, which we named tilimycin. For further studies, we were searching for a synthetic access to tilimycin and its derivative. Starting with 3-hydroxyanthranilic acid, we were able to synthesize the desired compound in a simple three-step procedure. Furthermore, it could be demonstrated that tilimycin is the precursor in the biosynthesis of tilivalline which is spontaneously formed by a nucleophilic attack of free indole. Recently, we synthesized 15N-labelled tilimycin and tilivalline, which successfully have been used as internal standards for simultaneous quantification of both metabolites in complex biological matrices.
Period15 Dec 2020
Event title12th ÖGMBT Annual Meeting: Biomolecules in/for the 21st century
Event typeConference
LocationGraz, Austria
Degree of RecognitionNational

Treatment code (Nähere Zuordnung)

  • Basic - Fundamental (Grundlagenforschung)

Fields of Expertise

  • Human- & Biotechnology

Keywords

  • Tilimycin
  • Tilivalline
  • Klebsiella Oxytoca

ASJC Scopus subject areas

  • Organic Chemistry