Auranofin potentiates linezolid activity against MRSA by disrupting redox homeostasis and inhibiting SarA-mediated virulence and biofilm

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major therapeutic challenge and poses a significant global health threat. Developing adjuvants to enhance the efficacy of existing antibiotics represents a promising strategy to address this issue. In this study, we evaluated auranofin as an adjuvant to potentiate the activity of linezolid against MRSA. Auranofin significantly increased MRSA susceptibility to linezolid, promoted intracellular linezolid accumulation, and suppressed the emergence of MRSA resistance to linezolid. Mechanistically, auranofin inhibited the Trx/TrxR system, inducing redox imbalance and reactive oxygen species (ROS) accumulation, which triggers DNA damage and transcriptional dysregulation. Auranofin synergized with linezolid to achieve dual inhibition of MRSA protein synthesis. Furthermore, auranofin downregulated the global regulator sarA, impaired SarA DNA-binding activity, and enhanced SarA phosphorylation, thereby attenuating SarA-mediated virulence factors (eg, adhesins and toxins) and biofilm formation. Importantly, auranofin fully restored anti-MRSA activity of linezolid in both Galleria mellonella and murine bacteremia models. Collectively, these findings identify auranofin as a promising adjuvant to linezolid and highlight its potential to improve therapeutic outcomes against invasive MRSA infections.耐甲氧西林金黄色葡萄球菌（Methicillin-resistant Staphylococcus aureus, MRSA）仍是临床治疗的重大挑战，亦构成重大的全球公共健康威胁。开发佐剂以增强现有抗生素的疗效，是解决该问题的极具前景的策略。本研究评估了金诺芬（auranofin）作为佐剂，增强利奈唑胺（linezolid）对抗MRSA的活性。结果显示，金诺芬可显著提升MRSA对利奈唑胺的敏感性，促进细胞内利奈唑胺的蓄积，并抑制MRSA对利奈唑胺耐药性的产生。机制层面，金诺芬可抑制硫氧还蛋白/硫氧还蛋白还原酶（Trx/TrxR）系统，诱导氧化还原失衡与活性氧（reactive oxygen species, ROS）蓄积，进而触发DNA损伤与转录失调。金诺芬与利奈唑胺协同作用，实现对MRSA蛋白质合成的双重抑制。此外，金诺芬可下调全局调控因子sarA，削弱SarA的DNA结合活性，并增强其磷酸化水平，从而减弱SarA介导的毒力因子（如黏附素与毒素）产生及生物膜形成。值得注意的是，在大蜡螟（Galleria mellonella）与小鼠菌血症模型中，金诺芬均可完全恢复利奈唑胺的抗MRSA活性。综上，本研究结果表明金诺芬是一种极具潜力的利奈唑胺佐剂，凸显了其用于改善侵袭性MRSA感染治疗效果的应用前景。