Abstract

Despite the suspected importance of horizontal gene transfer in creating the global public health crisis of AMR , this has yet to be evidenced or studied at a population level. Here we used Shigella, one of the top dozen AMR organisms, in high-risk men who have sex with men (MSM), an epidemiological network with enhanced transmission and antimicrobial usage rates, to study AMR emergence. We show that horizontal transfer of AMR drives new epidemics, and that the success of epidemic emergence is constrained by the genetic context of the AMR . We found that overlapping multi-species epidemics of MSM -associated Shigella were attributable to six genomic sublineages, all associated with azithromycin resistance. The four epidemiologically-successful sublineages carried this resistance on an identical plasmid that had horizontally transmitted from yet another globally-disseminated MSM -associated Shigella. The horizontal plasmid transmission rapidly drove epidemics of new sublineages, contrasting with the vertically-inherited resistance to ciprofloxacin; the recommend treatment for shigellosis. This transforms our understanding of the processes surrounding AMR emergence, and calls for a shift toward studying AMR with respect to its genetic context.