Integrated control of MRSA biological contamination via SarA-targeting γ-mangostin: A green natural antimicrobial strategy.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major public health threat owing to its pronounced antibiotic resistance, multiple virulence factors, and robust biofilm-forming capacity, yet effective integrated antimicrobial strategies are still lacking. The global regulator SarA serves as a regulatory hub that simultaneously governs these key MRSA hazard determinants. Here, we report a comprehensive platform for the all-round control of MRSA biological contamination, centered on a label-free electrochemical impedance spectroscopy (EIS)-based biosensing system designed to screen inhibitors targeting SarA. Using this platform, the fruit-derived flavonoid γ-mangostin (γ-MG) was identified as a potent SarA inhibitor. Further MD simulations revealed that γ-MG spontaneously and stably engaged residues within the DNA-binding domain, particularly VAL68 and VAL92, thereby attenuating structural fluctuations. γ-MG markedly reduced MRSA viability (MIC=8 μg/mL) inhibited biofilm formation, and effectively eliminated MRSA in milk. γ-MG quenched the intrinsic fluorescence of SarA and elicited a substantially greater impedance response at the SarA-modified gold electrode (ΔZ'=6.442 kΩ) relative to the positive control Morin (ΔZ'=1.614 kΩ). Transcriptomic and bioinformatic analyses revealed broad perturbation of SarA-regulated pathways, encompassing transcriptional activity, cell adhesion, stress response, and cell wall homeostasis, a profile closely resembling that of the ΔsarA mutant. Animal infection models confirmed the therapeutic efficacy and decontamination capacity of γ-MG against MRSA. Collectively, this study provides an effective strategy and a sensitive analytical tool for the integrated prevention and control of MRSA contamination.