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Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut
Journal
Nature
Volume
573
Number
7773
Pages / Article-Number
276-280
Mesh terms
Animals; Anti-Bacterial Agents, pharmacology; Drug Resistance, Bacterial, genetics; Escherichia coli, drug effects, genetics; Feces, microbiology; Gastrointestinal Microbiome, drug effects, genetics; Gene Transfer, Horizontal; Intestinal Mucosa, microbiology; Mice; Models, Theoretical; Plasmids, genetics; Salmonella typhimurium, drug effects, genetics; Vaccination
Abstract
The emergence of antibiotic-resistant bacteria through mutations or the acquisition of genetic material such as resistance plasmids represents a major public health issue; 1,2; . Persisters are subpopulations of bacteria that survive antibiotics by reversibly adapting their physiology; 3-10; , and can promote the emergence of antibiotic-resistant mutants; 11; . 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 microbiota; 12; . 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.
