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eSymposia | Harnessing the Microbiome for Disease Prevention and Therapy


Klebsiella oxytoca´s genotoxin tilimycin disrupts intestinal homeostasis


Jan 18, 2021 12:00am ‐ Jan 18, 2021 12:00am

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Klebsiella oxytoca´s genotoxin tilimycin disrupts intestinal homeostasis Kienesberger, S.1,3, Kitsera, M.1, Cosic, A.1, Halwachs, B.2, Leitner, E.2, Raffl, S.1, Glabonjat, R.A.1, Schild, S.1,3 and Zechner, E.L.1,3 1University of Graz, Austria, 2Medical University of Graz, Graz, Austria, and 3BioTechMed Graz Pathobiont Klebsiella oxytoca causes antibiotic-associated hemorrhagic colitis (AAHC) through production of two non-ribosomal peptide metabolites, each of which induces epithelial apoptosis (1). Tillivaline (TV) stabilizes microtubules and tilimycin (TM) forms covalent adducts with DNA causing lesions and DNA strand breaks (2). In this study we ask how the genotoxic activity of this pathobiont impacts microbial community structure and specifically address whether DNA stress due to TM generates mutations and genetic instability in the gut. To gain insight into the susceptibility of the fecal microbiota to TM we exposed human stool samples to physiological concentrations (3) for 2 h in vitro followed by differential plating. Growth inhibition was observed for nearly all bacterial taxa present and most notably for Bacteroidetes and Proteobacteria. The mechanism underlying poor survival was apparently DNA damage as exposure to TM induced SOS and generated mutations in Escherichia coli MG1655 at sequences containing the preferred TM binding motif (4). DNA stress in TM-treated Vibrio cholerae strains led to mutational antibiotic resistance emergence, activation of resident phage and increased transduction. Colonization of the mouse intestine with wild type or nps mutant K. oxytoca revealed TM-dependent alterations in 16S metagenomic data. TM+ K. oxytoca had a competitive advantage in the mouse when challenged with a murine isolate of E. coli and TM-dependent emergence of rifampicin resistance in this strain in vivo was used to monitor increased frequencies of mutation. We conclude that synthesis of a DNA damaging antibiotic by a resident pathobiont can promote genetic instability in commensals and pathogens alike. 1) Schneditz, G. et al. (2014) PNAS. 111(36)13181-13186 2) Unterhauser K., et al. (2019) PNAS 116(9)3774-3783 3) Glabonjat, R.A. (2021) Talanta. (222)121677 4) Evan, M.A. (2020) ACS Infect. Dis. (6)1976−1997

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