Emergence and spread of ST5 methicillin-resistant Staphylococcus aureus with accessory gene regulator dysfunction: genomic insights and antibiotic resistance.

The globally disseminated Staphylococcus aureus ST5 clone poses a major public health threat due to its multidrug resistance and virulence. Here, we identified an agr-dysfunctional (agrA-I238K) ST5 MRSA clone that has spread across East and Southeast Asia, with recent increases in China since its emergence in the 1970s. Comparative genomic analyses identified distinct single-nucleotide polymorphisms and mobile genetic elements linked to enhanced resistance and virulence. This clone exhibits resistance to seven antimicrobial classes, including third-generation tetracyclines and fusidic acid, and shares phenotypic and genetic similarities with the vancomycin-intermediate S. aureus Mu50 strain, including reduced susceptibility to vancomycin, teicoplanin, and daptomycin. The agrA-I238K mutation attenuates hemolytic activity, increases biofilm formation, and reduces daptomycin susceptibility, suggesting a key role in the clone's success. Our results demonstrate the important role of agrA-I238K mutation in the widespread distribution of agr-dysfunctional MRSA and highlight the importance of genomic surveillance in tracking the spread of agr-dysfunctional ST5 MRSA.