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Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut.

  • Bakkeren E Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland.
  • Huisman JS Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.
  • Fattinger SA Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland.
  • Hausmann A Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland.
  • Furter M Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland.
  • Egli A Division of Clinical Microbiology, University Hospital Basel, Basel, Switzerland.
  • Slack E Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland.
  • Sellin ME Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
  • Bonhoeffer S Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.
  • Regoes RR Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.
  • Diard M Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland. mederic.diard@unibas.ch.
  • Hardt WD Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland. hardt@micro.biol.ethz.ch.
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  • 2019-09-06
Published in:
  • Nature. - 2019
Animals
Anti-Bacterial Agents
Drug Resistance, Bacterial
Escherichia coli
Feces
Gastrointestinal Microbiome
Gene Transfer, Horizontal
Intestinal Mucosa
Mice
Models, Theoretical
Plasmids
Salmonella typhimurium
Vaccination
English The emergence of antibiotic-resistant bacteria through mutations or the acquisition of genetic material such as resistance plasmids represents a major public health issue1,2. Persisters are subpopulations of bacteria that survive antibiotics by reversibly adapting their physiology3-10, and can promote the emergence of antibiotic-resistant mutants11. We investigated whether persisters can also promote the spread of resistance plasmids. In contrast to mutations, the transfer of resistance plasmids requires the co-occurrence of both a donor and a recipient bacterial strain. For our experiments, we chose the facultative intracellular entero-pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) and Escherichia coli, a common member of the microbiota12. S. Typhimurium forms persisters that survive antibiotic therapy in several host tissues. Here we show that tissue-associated S. Typhimurium persisters represent long-lived reservoirs of plasmid donors or recipients. The formation of reservoirs of S. Typhimurium persisters requires Salmonella pathogenicity island (SPI)-1 and/or SPI-2 in gut-associated tissues, or SPI-2 at systemic sites. The re-seeding of these persister bacteria into the gut lumen enables the co-occurrence of donors with gut-resident recipients, and thereby favours plasmid transfer between various strains of Enterobacteriaceae. We observe up to 99% transconjugants within two to three days of re-seeding. Mathematical modelling shows that rare re-seeding events may suffice for a high frequency of conjugation. Vaccination reduces the formation of reservoirs of persisters after oral infection with S. Typhimurium, as well as subsequent plasmid transfer. We conclude that-even without selection for plasmid-encoded resistance genes-small reservoirs of pathogen persisters can foster the spread of promiscuous resistance plasmids in the gut.
Language
  • English
Open access status
green
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https://sonar.ch/global/documents/136329
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