Pre- and postantibiotic epoch: The historical spread of antimicrobial resistance

Plasmids are now the primary vectors of antimicrobial resistance, but our understanding of how human industrialisation of antibiotics influenced their evolution is limited by a paucity of data predating the antibiotic era (PAE). By investigating plasmids from clinically relevant bacteria sampled and isolated between 1917 and 1954 and comparing them to modern plasmids, we have captured over 100 years of evolution. We show that while virtually all PAE plasmids were devoid of resistance genes and most never acquired them, a minority evolved to drive the global spread of resistance to first line and last resort antibiotics in Gram-negative bacteria. Modern plasmids have evolved through complex microevolution and fusion events into a distinct group of highly recombinogenic, multi-replicon, self-transmissible plasmids that now pose the highest risk to resistance dissemination, and therefore to human health.