Piggybacking on niche-adaptation improves the maintenance of multidrug resistance plasmids.

The persistence of plasmids in bacterial populations represents a puzzling evolutionary problem with serious clinical implications due to their role in the ongoing antibiotic resistance crisis. Recently, major advancements have been made towards resolving this "plasmid paradox" but mainly in a non-clinical context. Here we propose an additional explanation for the maintenance of multidrug resistance (MDR) plasmids in clinical Escherichia coli strains. After co-evolving two MDR plasmids encoding last resort carbapenem resistance with an extraintestinal pathogenic E. coli strain, we observed that chromosomal media adaptive mutations in the global regulatory systems CCR (Carbon Catabolite Repression) and ArcAB (Aerobic Respiration Control) pleiotropically improved the maintenance of both plasmids. Mechanistically, a net downregulation of plasmid gene expression reduced the fitness cost. Our results suggest that global chromosomal transcriptional re-wiring during bacterial niche-adaptation may facilitate plasmid maintenance.