Berberine modulates virulence gene expression in methicillin-resistant Staphylococcus aureus through the Agr system

Methicillin-resistant Staphylococcus aureus (MRSA) infection remains a major global health challenge, with its high pathogenicity largely attributed to a wide array of virulence factors. The accessory gene regulator (Agr) quorum-sensing system acts as a central hub for regulating virulence gene expression in MRSA, making it an attractive target for anti-virulence therapeutic strategies. This study investigated the inhibitory effect of the natural compound berberine (BBR) on MRSA virulence. Quantitative Real-time polymerase chain reaction (qRT-PCR) revealed that BBR significantly suppressed Agr system activity, leading to marked downregulation of key virulence genes, including α -Hemolysin (also known as α-toxin or Hla), Phenol-soluble modulin α ( psmα ), and Clumping factor A ( clfA ). Phenotypic assays confirmed that BBR treatment reduced hemolytic activity, biofilm formation, and host cell invasion. In a murine model of MRSA-induced pneumonia, BBR provided notable protective effects, as evidenced by reduced lung tissue damage, diminished inflammatory cell infiltration, and preservation of alveolar structure. Furthermore, BBR attenuated excessive production of pro-inflammatory cytokines and chemokines. Collectively, these findings demonstrate that BBR suppresses MRSA virulence by targeting the Agr quorum-sensing system. This highlights its potential as a novel anti-virulence agent or as a complementary approach to conventional antibiotic therapy, offering a promising strategy for managing MRSA infections.