Emergence and genomic adaptation of the globally disseminated ST2250 lineage within the <i>Staphylococcus aureus</i> complex

<i>Staphylococcus argenteus</i>, a member of the <i>S. aureus</i> complex, is increasingly recognized as a globally distributed pathogen with significant clinical relevance. Among its lineages, sequence type (ST) 2250 has emerged as the most prevalent and geographically widespread, yet its evolutionary history and genomic adaptations remain incompletely understood. In this study, we conducted a comprehensive genomic analysis of 277 ST2250 genomes from 26 countries between 2008 and 2025, integrating 14 newly sequenced isolates from China. Phylogenetic reconstruction resolved a basal clade I around 1989 and sister clades II and III that diversified later, in approximately 1996 and 1997, with frequent cross-regional, intercontinental, and cross-host transmission events. A methicillin-resistant <i>S. argenteus</i> subclade within clade II likely arose from a single SCC<i>mec</i> IVc acquisition, accompanied by a <i>blaZ</i>-carrying plasmid. Clade III genomes carried a related multidrug-resistant (MDR) plasmid encoding <i>blaZ</i>, <i>tet</i>(L), and <i>aph(3')-III</i>; Bayesian phylogenetic inference indicated that this plasmid was introduced into the ancestor of the clade III MDR subclade around 2001, potentially promoting its subsequent expansion. Both clades also exhibited enriched virulence profiles, particularly the secretion system gene <i>esaG7</i>. Despite the widespread presence of active defense systems that might limit the acquisition of mobile genetic elements, the ST2250 pan-genome remains open, with evidence of active gene flux and convergent selection targeting resistance, virulence, and metabolic pathways. These findings elucidate the global spread, ecological plasticity, and adaptive evolution of ST2250, providing critical genomic insights into the emergence and persistence of this lineage.