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

Erik Bakkeren, Jana S. Huisman, Stefan A. Fattinger, Annika Hausmann, Markus Furter, Adrian Egli, Emma Slack, Mikael E. Sellin, Sebastian Bonhoeffer, Roland R. Regoes, Médéric Diard () and Wolf-Dietrich Hardt ()
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Erik Bakkeren: ETH Zurich
Jana S. Huisman: ETH Zurich
Stefan A. Fattinger: ETH Zurich
Annika Hausmann: ETH Zurich
Markus Furter: ETH Zurich
Adrian Egli: University Hospital Basel
Emma Slack: ETH Zurich
Mikael E. Sellin: Uppsala University
Sebastian Bonhoeffer: ETH Zurich
Roland R. Regoes: ETH Zurich
Médéric Diard: ETH Zurich
Wolf-Dietrich Hardt: ETH Zurich

Nature, 2019, vol. 573, issue 7773, 276-280

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1521-8

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