Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut
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 physiology3,4,5,6,7,8,9,10, 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.
Data availability
The genome and plasmid sequence of E. coli ESBL 15 have been deposited in GenBank under accession numbers CP041678–CP041681 (Biosample SAMN12275742). Numerical Source Data for all figures are provided with the paper. Source images are available upon request to the corresponding authors.
Code availability
Code for the stochastic simulation of plasmid-transfer dynamics and parameter estimation from the experimental data are provided with the paper. The R code follows the notation used in the Supplementary Information.
Acknowledgements
We thank the members of the Hardt, Slack, Bonhoeffer, Stadler and Ackermann labs for helpful discussion, and the staff at the RCHCI and EPIC animal facilities for their excellent support. This work has been funded, in part, by grants from the Swiss National Science Foundation (SNF; 310030B-173338), the Promedica Foundation, Chur and the Helmut Horten Foundation to W.-D.H., and from the SNF NFP 72 (407240-167121) to W.-D.H., S.B. and A.E. M.D. is funded by an SNF professorship grant (PP00PP_176954), E.B. by a Boehringer Ingelheim Fonds PhD fellowship, and M.E.S. and S.A.F. (in part) by the Swedish Research Council (2015-00635, 2018-02223). R.R.R. is funded by SNF grant number 31003A_179170. E.S. is supported by grant GRS 073/17 from the ‘Microbials’ programme of the Gebert Rüf Foundation and the SNF Bridge Discover Grant 20B2-1 180953.
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