Host range and ARG 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 from public databases and found that two distinct survival strategies were enriched in different host-range groups: a “stealth” strategy, which minimizes host fitness costs by employing a global regulator h-ns , was particularly enriched in broad-host-range plasmids, whereas an “aggressive” strategy, which protects plasmids by actively inhibiting host response including SOS response by encoding the SOS inhibitor psiB , was more common in narrow-host-range plasmids. Plasmids employing either strategy constituted the majority of all 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 aggressive 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.