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The global rise in antimicrobial resistance (AMR) is a critical public health issue, with methicillin-resistant Staphylococcus aureus (MRSA) being a key player. MRSA causes severe infections, including pneumonia and septic arthritis. This study investigates MgrA, a transcription factor that regulates S. aureus multidrug resistance and virulence, identifying negletein as a potent MgrA inhibitor. Negletein's ability to modulate virulence without directly killing bacteria introduces a novel strategy to combat multidrug resistance. It disrupts S. aureus adhesion and invasion by interfering with the Agr system and altering surface protein expression, preventing infection. Additionally, negletein enhances host immune responses by increasing neutrophil chemotaxis. Confirmed through thermal shift assays and fluorescence quenching, negletein’s interaction with MgrA reveals key binding residues. In vitro and in vivo studies demonstrated that negletein offers dose-dependent protection against MRSA, significantly improving survival rates and reducing bacterial burden in infection models. Notably, negletein showed therapeutic effects on MRSA-induced septic arthritis. These findings underscore negletein's potential as a novel treatment for MRSA-induced infections, providing an innovative approach to tackle multidrug-resistant infections and advancing new paradigms in AMR treatment.