Nanoantibiotic copper-cefazolin combats MRSA infection through a reverse Trojan horse strategy

Cefazolin (CZO) is a first-line prophylactic antibiotic used during the perioperative period; however, upregulation of bacterial efflux pump expression accelerates the development of CZO resistance. This study developes a nanoantibiotic (Cu-CZO) that employs a "reverse Trojan horse" strategy to combat antimicrobial-resistant bacterial infections. Disguised as a "Trojan horse" for CZO in this reverse Trojan horse approach, Cu-CZO disrupts the bacterial copper transport system, leading to downregulation of the CopA transporter. This suppresses copper efflux and inhibits the active efflux of CZO, culminating in the intracellular accumulation of Cu-CZO. This study demonstrates that Cu-CZO effectively accumulates within bacteria and eradicates methicillin-resistant Staphylococcus aureus (MRSA)-induced subcutaneous abscesses. Furthermore, it significantly enhances tissue regeneration and functional recovery in infected wounds. This nanoantibiotic overcomes the key resistance mechanism of active CZO efflux in antimicrobial-resistant bacteria, thereby presenting a novel paradigm for fundamentally addressing antibiotic resistance and extending the clinical lifespan of existing antibiotics.