Tuning Ligands Ratio Allows for Controlling Gold Nanocluster Conformation and Activating a Nonantimicrobial Thiol Fragrance for Effective Treatment of MRSA‐Induced Keratitis

Abstract Bacterial keratitis is a serious ocular disease that affects millions of people worldwide each year, among which ≈25% are caused by Staphylococcus aureus. With the spread of bacterial resistance, refractory keratitis caused by methicillin‐resistant S. aureus (MRSA) affects ≈120 000–190 000 people annually and is a significant cause of infectious blindness. Atomically precise gold nanoclusters (GNCs) recently emerged as promising antibacterial agents; although how the GNC structure and capping ligands control the antibacterial properties remains largely unexplored. In this study, by adjusting the ratio of a “bulky” thiol fragrance to a linear zwitterionic ligand, the GNC conformation is transformed from Au₂₅(SR)₁₈ to Au₂₃(SR)₁₆ species, simultaneously converting both inactive thiol ligands into potent antibacterial nanomaterials. Surprisingly, mixed‐ligand capped Au₂₃(SR)₁₆ GNCs exhibit superior antibacterial potency compared to their monoligand counterparts. The optimal GNC is highly potent against MRSA, showing >1024‐fold lower minimum inhibitory concentration than the corresponding free ligands. Moreover, it displays excellent potency in treating MRSA‐induced keratitis in mice with greatly accelerated corneal recovery (by approximately ninefold). Thus, this study establishes a feasible method to synthesize antibacterial GNCs by adjusting the ligand ratio to control GNC conformation and active non‐antibacterial ligands, thereby greatly increasing the repertoires for combating multidrug‐resistant bacterial infections.