Host range and antibiotic resistance dissemination are shaped by distinct survival strategies of conjugative plasmids

Horizontal gene transfer is a major driver of bacterial evolution and the global dissemination of antibiotic resistance genes (ARGs). Conjugative plasmids play a crucial role in ARG spread across hosts within their host range, yet the genetic and functional determinants shaping plasmid host range remain poorly understood. Here, we systematically analyzed the gene content of conjugative/mobilizable plasmids derived from Enterobacterales from public databases and found that two distinct survival strategies were enriched in different host-range groups: a "stealth" strategy, which actively represses its own transcription by employing a global regulator hns, was particularly enriched in broad-host-range plasmids, whereas a "manipulative" strategy, which promotes its establishment by manipulating host machineries including SOS response and defense systems, was more common in narrow-host-range plasmids. Plasmids employing either strategy constituted the majority of conjugative plasmids analyzed, and accumulated significantly more ARGs than plasmids with neither strategy. Our data further suggested that stealth plasmids facilitate the acquisition of emerging ARGs, while manipulative plasmids amplify the copy number of established ARGs. This "stealth-first" model successfully recapitulated historical ARG dissemination patterns. These findings provide critical insights into the relationship between plasmid survival strategies and host range, advancing our understanding of the global patterns underlying plasmid-mediated ARG transmission.