Enterotoxin tilimycin from gut-resident Klebsiella promotes mutational evolution and antibiotic resistance in mice

Sabine Kienesberger, Amar Cosic, Maksym Kitsera, Sandra Raffl, Marlene Hiesinger, Eva Leitner, Bettina Halwachs, Gregor Gorkiewicz, Ronald A Glabonjat, Georg Raber, Christian Lembacher-Fadum, Rolf Breinbauer, Stefan Schild, Ellen L Zechner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Klebsiella spp. that secrete the DNA-alkylating enterotoxin tilimycin colonize the human intestinal tract. Numbers of toxigenic bacteria increase during antibiotic use, and the resulting accumulation of tilimycin in the intestinal lumen damages the epithelium via genetic instability and apoptosis. Here we examine the impact of this genotoxin on the gut ecosystem. 16S rRNA sequencing of faecal samples from mice colonized with Klebsiella oxytoca strains and mechanistic analyses show that tilimycin is a pro-mutagenic antibiotic affecting multiple phyla. Transient synthesis of tilimycin in the murine gut antagonized niche competitors, reduced microbial richness and altered taxonomic composition of the microbiota both during and following exposure. Moreover, tilimycin secretion increased rates of mutagenesis in co-resident opportunistic pathogens such as Klebsiella pneumoniae and Escherichia coli, as shown by de novo acquisition of antibiotic resistance. We conclude that tilimycin is a bacterial mutagen, and flares of genotoxic Klebsiella have the potential to drive the emergence of resistance, destabilize the gut microbiota and shape its evolutionary trajectory.

Original languageEnglish
Pages (from-to)1834-1848
JournalNature Microbiology
Volume7
Issue number11
DOIs
Publication statusPublished - Nov 2022

Keywords

  • Mice
  • Humans
  • Animals
  • Klebsiella/genetics
  • Enterotoxins
  • RNA, Ribosomal, 16S/genetics
  • Ecosystem
  • Drug Resistance, Microbial
  • Anti-Bacterial Agents/pharmacology
  • Escherichia coli/genetics

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Microbiology (medical)
  • Genetics
  • Cell Biology
  • Microbiology
  • Immunology

Fields of Expertise

  • Human- & Biotechnology

Cooperations

  • BioTechMed-Graz

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