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Published on: December 10, 2016
Enterotoxin tilimycin from gut-resident Klebsiella promotes mutational evolution and antibiotic resistance in mice
Sabine Kienesberger1,2,3, Amar Cosic1, Maksym Kitsera1
1Institute of Molecular Biosciences, University of Graz, Graz, Austria.
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.
Insights
The bacterial toxin tilimycin, secreted by Klebsiella, acts as a mutagen in the gut. This genotoxin promotes antibiotic resistance and disrupts the gut microbiota composition and stability.
Area of Science:
- Microbiology
- Genetics
- Gut Microbiome Research
Background:
- Klebsiella spp. colonize the human gut and secrete the DNA-alkylating enterotoxin tilimycin.
- Antibiotic use increases toxigenic bacteria, leading to tilimycin accumulation and gut epithelial damage via genetic instability and apoptosis.
Purpose of the Study:
- To investigate the impact of the genotoxin tilimycin on the gut ecosystem.
- To understand tilimycin's role as a pro-mutagenic agent and its effects on microbial communities.
Main Methods:
- 16S rRNA sequencing of faecal samples from colonized mice.
- Mechanistic analyses to determine tilimycin's effects on microbial populations and mutagenesis.
Main Results:
- Tilimycin was identified as a pro-mutagenic antibiotic affecting multiple bacterial phyla.
- Transient tilimycin synthesis reduced microbial richness, altered taxonomic composition, and antagonized niche competitors.
- Tilimycin secretion accelerated mutagenesis in opportunistic pathogens, leading to de novo antibiotic resistance acquisition.
Conclusions:
- Tilimycin functions as a bacterial mutagen.
- Genotoxic Klebsiella flares can drive antibiotic resistance emergence.
- Tilimycin has the potential to destabilize the gut microbiota and influence its evolutionary path.
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