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

The above results collectively indicate that the influx of Cu-CZO into the bacterial interior mediates the upregulation of CsoR in MRSA, which in turn leads to the downregulation of ctpV expression and that the amount of CopA alone has difficulty maintaining Cu2+ homeostasis within the bacterium, with increased intracellular Cu2+ and disorganization of copper metabolism; furthermore, the duration of action of CZO within the bacteria is prolonged, and the dual action of copper toxicity and CZO kills the bacteria. This key mechanism can be further investigated by conducting CopA functional validation in conjunction with the evaluation of the nanoantibiotic efflux capacity.上述研究结果共同表明，铜-头孢唑啉（Cu-CZO）进入细菌内部后，可介导耐甲氧西林金黄色葡萄球菌（MRSA）中CsoR的表达上调；该过程继而会导致ctpV基因的表达下调，且仅靠CopA蛋白难以维持细菌内的Cu²+稳态，进而造成胞内Cu²+水平升高、铜代谢紊乱。此外，头孢唑啉（CZO）在细菌内的作用时长得以延长，铜毒性与头孢唑啉的双重作用可杀灭细菌。该核心机制可通过开展CopA蛋白功能验证，并结合纳米抗生素外排能力评估进行进一步研究。