Distinct genetic programs drive antibiotic resistance and intracellular invasion in emerging MRSA strains

Methicillin-resistant Staphylococcus aureus (MRSA) is a major global health threat because of its ability to adapt. In North America, the USA300 lineage ST8 has become the predominant MRSA clone, whereas the ST72 lineage has emerged as an important MRSA in East Asia. Here, we compare USA300 and SAWL001 from the ST72 at the phenotypic, genomic, and transcriptomic levels. Phenotypic assays assessed antibiotic susceptibility, intracellular invasion, oxidative stress survival, biofilm formation under β-lactam exposure, blood-induced cell clumping, persister formation, and virulence in a mouse sepsis model. For genomic analyses, we compared the SAWL001 genome against USA300 and other major S. aureus strains. SAWL001 showed modestly higher resistance to rifampicin, gentamicin, and linezolid compared with USA300. We also found that SAWL001 mecA is inducible only under oxacillin, whereas USA300 mecA is constitutively expressed. Consistent with these differences, SAWL001 invaded human epithelial cells far less efficiently and survived H₂O₂ exposure at a significantly lower rate than USA300. Furthermore, our genome analysis revealed that SAWL001 has features different from USA300, such as the beta-lactamase gene locus. Finally, our transcriptomic profiling shows that USA300 maintains virulence features such as PVL, while SAWL001 shows adaptation toward greater horizontal gene transfer and antibiotic resistance. Together, our findings highlight that MRSA lineages can branch toward different evolutionary trajectories, such as becoming more antibiotic resistant or more invasive, underscoring the need for lineage-specific analysis to identify competence determinants and to tailor treatment strategies to each clone's strengths and weaknesses.IMPORTANCEMethicillin-resistant Staphylococcus aureus remains a leading cause of antibiotic-resistant infections worldwide, and its lineages can differ widely in antibiotic resistance and virulence. In this study, we compared the North American USA300 lineage (ST8) with an emerging East Asian ST72 strain, SAWL001. SAWL001 showed higher resistance to several antibiotics than USA300, although the overall resistance levels were moderate. Also, SAWL001 exhibits an inducible mecA-mediated methicillin resistance, whereas USA300 expresses mecA constitutively. Conversely, USA300 invades host epithelial cells more effectively and survives oxidative stress better than SAWL001. Genome and transcriptome analyses show that USA300 retains classical virulence factors, while SAWL001 is primed for horizontal gene acquisition. Our findings underscore distinct evolutionary strategies: USA300 appears to favor aggressive virulence, whereas SAWL001 shows greater metabolic and genomic flexibility, suggesting the need for lineage-specific control strategies.