The protective effect of Schisandrin C against methicillin-resistant Staphylococcus aureus-induced otitis media.

Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen in otitis media (OM), including acute otitis media (AOM) and chronic suppurative otitis media (CSOM), presenting considerable therapeutic challenges due to its biofilm formation, host immune evasion, and promotion of persistent inflammation. This study evaluated the therapeutic potential of Schisandrin C (Sch C), a natural lignan derived from Schisandra chinensis, in mitigating MRSA-induced OM. In rat models of MRSA-induced AOM and CSOM, Sch C significantly reduced bacterial load and inflammatory responses by decreasing pro-inflammatory cytokine levels. By upregulating tight junction protein ZO-1 and downregulating mucin MUC5B, it also restored epithelial barrier integrity. In addition, Sch C treatment improved auditory function. Mechanistic studies revealed that Sch C directly inhibited sortase A (SrtA), a key enzyme responsible for anchoring surface virulence factors in MRSA, by binding to its active site and inhibiting its transpeptidase activity (fluorescence resonance energy transfer IC₅₀ = 38.68 µM). Through inhibiting SrtA, Sch C disrupted MRSA adhesion, invasion, and biofilm formation without exerting direct bactericidal effects. Furthermore, Sch C synergized with ofloxacin, enhancing its efficacy against MRSA otitis by reducing bacterial load, inflammation, and tissue damage. Collectively, these findings establish Sch C as a potent S. aureus SrtA inhibitor, highlighting its promise as a therapeutic strategy for MRSA-induced OM.