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Bacterial interspecies interactions modulate pH-mediated antibiotic tolerance in a model gut microbiota

By Andres Aranda-Diaz, Benjamin Obadia, Tani Thomsen, Zachary F Hallberg, Zehra Tuzun Guvener, Kerwyn Casey Huang, William B Ludington

Posted 01 Feb 2019
bioRxiv DOI: 10.1101/538132

Despite decades of investigation into how antibiotics affect isolated bacteria, it remains highly challenging to predict consequences for communities in complex environments such as the human intestine. Interspecies interactions can impact antibiotic activity through alterations to the extracellular environment that change bacterial physiology. By measuring key metabolites and environmental pH, we determined that metabolic cross-feeding among members of the fruit fly gut microbiota drives changes in antibiotic sensitivity in vitro. Co-culturing of Lactobacillus plantarum with Acetobacter species induced tolerance to rifampin. Mechanistically, we found that acetobacters counter the acidification driven by L. plantarum production of lactate, and that pH shifts during stationary phase were sufficient to drive rifampin tolerance in L. plantarum monocultures. The key Lactobacillus physiological parameter related to tolerance was a reduction in lag time exiting stationary phase, opposite to a previously identified mode of tolerance to ampicillin in E. coli. Lactobacillus tolerance to erythromycin also depended on growth status and pH, suggesting that our findings generalize to other antibiotics. Finally, tolerance of L. plantarum to rifampin varied spatially across the fruit fly gut. This mechanistic understanding of the coupling among interspecies interactions, environmental pH, and antibiotic tolerance enables future predictions of growth and the effects of antibiotics in more complex communities and within hosts.

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