H₂S-Driven Copper Redox Cycling Integrates Direct Bactericidal Activity and Macrophage Immunomodulation for Enhanced MRSA Clearance at Low-dose Copper
Description
This study reports a hydrogen sulfide (H₂S)-driven copper redox cycling system that synergizes direct bactericidal activity and macrophage immunomodulation for methicillin-resistant Staphylococcus aureus (MRSA) clearance in vitro at subtoxic copper doses. By coupling oxygen-mediated oxidation with sulfide-driven reduction, the system achieves self-sustaining Cu(II)/Cu(I) cycling, maintaining bioactive Cu(I) regeneration (30.8–50.6% reduction efficiency over 8 d) under physiological redox equilibrium. At an ultralow total copper dose (12.5 μM), the dual-action mechanism delivered 67.3% inhibition of extracellular MRSA growth in vitro, alongside 86.1% clearance of intracellular MRSA in cultured RAW264.7 macrophages, concomitant with Cu(I)-associated M1 polarization. Comparative in vitro assays demonstrated markedly enhanced intracellular MRSA clearance relative to Cu(II) monotherapy (86.1% vs. 14.3%), alongside M1 activation characterized by TNF-α upregulation (ELISA), IL-10 suppression in M2-polarized cells, and an M2-to-M1 phenotype transition (qRT-PCR). The system preserved host cell viability (>80%) in vitro and was associated with reduced MRSA-induced M2 polarization. These in vitro findings propose a metal-based antimicrobial strategy that integrates pathogen-targeting and host-directed actions and supports further evaluation of copper-dose reduction; efficacy in an infection model remains to be established.