Food-Derived Alkaloid Isoliensinine Mitigates Staphylococcus aureus-Triggered Joint Inflammatory Response and Tissue Damage

Isoliensinine, a bisbenzylisoquinoline alkaloid derived from the embryo of Nelumbo nucifera (lotus seed), is widely used in functional foods and traditional herbal infusions because of its anti-inflammatory and antioxidant properties. In this study, we explored its potential as a food-derived antivirulence agent against methicillin-resistant Staphylococcus aureus (MRSA), a clinically significant pathogen responsible for severe infections, including septic arthritis. Although MRSA is associated primarily with healthcare- and community-acquired infections, its occasional detection in food products such as meat and dairy raises public health concerns regarding its broader ecological distribution. In vitro, isoliensinine markedly suppressed MRSA cytotoxicity by inhibiting hemolysin activity, reducing bacterial adhesion and invasion, and downregulating key virulence gene expression without affecting bacterial growth—thus avoiding selective pressure for resistance. Mechanistic investigations via a cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and electrophoretic mobility shift assay (EMSA) confirmed that isoliensinine directly binds to SaeR, the response regulator of the SaeRS two-component system, and blocks its DNA-binding activity, thereby impairing the transcriptional control of multiple virulence determinants. In vivo efficacy was demonstrated in both Galleria mellonella and a rat model of MRSA-induced septic arthritis. Isoliensinine treatment significantly reduced the bacterial burden, alleviated synovial inflammation, and preserved cartilage and bone structure, indicating strong protective effects against infection-associated joint damage. Given its natural dietary origin, safety profile, and mechanistic specificity, isoliensinine has strong potential for development as a next-generation nutraceutical or functional food additive aimed at preventing or mitigating infections associated with virulent pathogens.