Emergent Antibiotic Persistence in Cross-Feeding Bacteria in Structured Habitats

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Antibiotic persistence allows a sub-population of bacteria to survive antibiotic-induced killing and contributes to the evolution of antibiotic resistance. Although bacteria typically live in microbial communities with complex ecological interactions, little is known about how microbial ecology affects antibiotic persistence. Here, we demonstrated that the combination of cross-feeding and community spatial structure can emergently cause high antibiotic persistence in bacteria by increasing the cell-cell heterogeneity in the metabolic state both during growth and antibiotic killing. We tracked the ampicillin-induced death on agar surfaces in a model obligate mutualism of Escherichia coli and Salmonella enterica . We found that E. coli formed ∼100-fold more antibiotic persisters in the cross-feeding coculture than in monoculture. This high persistence could not be explained solely by the presence of S. enterica , the presence of cross-feeding, or the growth rate differences between the mono- and co-cultures. Time-series fluorescent microscopy revealed increased cell-cell variation in E. coli lag time in the mutualistic co-culture. Furthermore, we discovered that an E. coli cell can survive antibiotic killing if the nearby S. enterica cells on which it relies die first—a mechanism we termed “dynamical loss of access to nutrient.” In conclusion, we showed that the high antibiotic persistence phenotype can be an emergent phenomenon caused by a combination of cross-feeding and spatial structure. Our work highlights the importance of considering spatially-structured interactions during antibiotic treatment and to understand microbial community resilience more broadly.

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  1. In the current study, we show that microbial ecology can affect antibiotic persistence. Our work highlights that microbial interactions and spatial structure can generate emergent increase in individual heterogeneity.

    Thank you for this very interesting work that addresses fascinating abilities of bacteria (microbial interactions, phenotypic heterogeneity and antibiotic persistence).

  2. In this work, we demonstrated that cross-feeding in a spatially-structured environment can increase antibiotic persistence by 32∼100-fold in both the mutualistic E. coli and S. enterica as compared to the monocultures

    This is a very nice and clear conclusion. Yet this has been only performed for 1 mutualistic 2-species community and for a single antibiotic. It would be interesting to know the authors' rational about choosing this antibiotic specifically, and why not extending these assays to different antibiotics and/or communities (yet I understand this is not that easy to find tractable mutualistic communities). Also, would the authors expect that this observation to be independent on the type of antibiotic?

  3. dynamical loss of access to nutrient” (DLAN)

    This is a very interesting observation. Do the authors have ideas/suggestions about the molecular mechanism/response? Would antibiotic persistence be associated with a broad stress response (like stress response, stringent response, entry to stationary phase for instance?), or do they expect it to be a more specific mechanism? Would there be a way to use microscopy to see if such broad responses are activated in persistent cells?