Disarming the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via Osmundacetone-Mediated Inhibition of Sortase A

Methicillin-resistant Staphylococcus aureus (MRSA) is a major global health threat due to its resistance to multiple antibiotics, making conventional treatments ineffective. The rise in antibiotic resistance highlights the urgent need for new therapies. Sortase A (SrtA), a key virulence factor in Staphylococcus aureus (S. aureus), facilitates bacterial adhesion and infection by anchoring surface proteins to host cells, making it a promising drug target. In this study, we investigated the potential of osmundacetone (OSC), a natural compound from Osmundae Rhizoma, as an SrtA inhibitor. Using fluorescence resonance energy transfer (FRET), OSC was found to inhibit SrtA with an IC₅₀ of 1.29 μg/mL (7.24 μM). Further in vitro assays confirmed the effectiveness of OSC in inhibiting SrtA-mediated bacterial adhesion, invasion and biofilm formation. Fluorescence quenching and molecular docking pinpointed the binding site of OSC on SrtA. In vivo, OSC improved survival rates in MRSA-infected mice and Galleria mellonella (G. mellonella) while reducing bacterial loads in infected tissues. These results suggest OSC as a promising candidate for anti-MRSA therapies.