Emerging patterns of plasmid-host coevolution that stabilize antibiotic resistance.

Multidrug resistant bacterial pathogens have become a serious global human health threat, and conjugative plasmids are important drivers of the rapid spread of resistance to last-resort antibiotics. Whereas antibiotics have been shown to select for adaptation of resistance plasmids to their new bacterial hosts, or vice versa, a general evolutionary mechanism has not yet emerged. Here we conducted an experimental evolution study aimed at determining general patterns of plasmid-bacteria evolution. Specifically, we found that a large conjugative resistance plasmid follows the same evolutionary trajectories as its non-conjugative mini-replicon in the same and other species. Furthermore, within a single host-plasmid pair three distinct patterns of adaptive evolution led to increased plasmid persistence: i) mutations in the replication protein gene (trfA1); ii) the acquisition by the resistance plasmid of a transposon from a co-residing plasmid encoding a putative toxin-antitoxin system; iii) a mutation in the host's global transcriptional regulator gene fur. Since each of these evolutionary solutions individually have been shown to increase plasmid persistence in other plasmid-host pairs, our work points towards common mechanisms of plasmid stabilization. These could become the targets of future alternative drug therapies to slow down the spread of antibiotic resistance.