Reduced MGE burden, virulence optimization, and acid stress tolerance shape the clonal succession of MRSA ST59

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) ST59 clone has replaced the historically dominant ST239 in China. However, the mechanisms behind this shift remain elusive. Phylogenetic analysis revealed divergent evolutionary trajectories: ST239 emerged via interlineage recombination and accumulated extensive resistance and genome degradation, whereas ST59 followed a more conserved, recombination-sparse path marked by reduced mobile genetic element (MGE) burden and retention of key virulence-associated MGEs. ST239's decline was attributed to the fitness costs of multidrug resistance, widespread pseudogenization, and a closed pan-genome. Furthermore, ST59 exhibited enhanced virulence. Two key virulence determinants were identified: deletion of <i>chp</i> impaired survival in whole blood and neutrophil cocultures by disrupting C5a-mediated chemotaxis; <i>sraP</i> deletion reduced epithelial adhesion, nasal colonization, and systemic virulence. ST59 also demonstrated superior acid tolerance, linked to transcriptomic activation of transport and metabolic pathways. Our findings highlight that the epidemiological success of clones requires a balance of reduced resistance, targeted virulence, and environmental adaptability.