Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections

Implant-associated infections (IAIs) caused by S. aureus can result in serious challenges after orthopedic surgery. Due to biofilm formation and antibiotic resistance, this refractory infection is highly prevalent, and finding drugs to attenuate bacterial virulence is becoming a rational alternative strategy. In S. aureus, the SaeRS two-component system (TCS) plays a key role in the production of over 20 virulence factors and the pathogenesis of the bacterium. Here, by conducting a structure-based virtual screening against SaeR, we identified that fenoprofen, a USA Food and Drug Administration (FDA)-approved nonsteroid anti-inflammatory drug (NSAID), had excellent inhibitory potency against the response regulator SaeR protein. We showed that fenoprofen attenuated the virulence of S. aureus without drug resistance. In addition, it was helpful in relieving osteolysis and restoring the walking ability of mice in vitro and in implant-associated infection models. More importantly, fenoprofen treatment suppressed biofilm formation and changed the biofilm structure, which caused S. aureus to form loose and porous biofilms that were more vulnerable to infiltration and elimination by leukocytes. Our results reveal that fenoprofen is a potent antivirulence agent with potential value in clinical applications and that SaeR is a drug target against S. aureus implant-associated infections.由金黄色葡萄球菌（S. aureus）引发的植入物相关感染（IAIs），可在骨科手术后引发严重的临床挑战。由于生物被膜形成与抗生素耐药性问题，这类难治性感染高发且难以根治，因此研发能够减弱细菌毒力的药物正成为一种合理的替代治疗策略。在金黄色葡萄球菌中，SaeRS双组分系统（TCS）在超过20种毒力因子的产生以及该细菌的致病进程中发挥关键作用。本研究通过针对SaeR开展基于结构的虚拟筛选，发现非那洛芬——一种已获美国食品药品监督管理局（FDA）批准的非甾体抗炎药（NSAID）——对应答调控蛋白SaeR具有优异的抑制活性。实验证实，非那洛芬可在不引发细菌耐药性的前提下减弱金黄色葡萄球菌的毒力。此外，在体外及植入物相关感染模型中，该药物有助于缓解小鼠骨溶解并恢复其行走能力。更为关键的是，非那洛芬处理可抑制生物被膜形成并改变其结构，使金黄色葡萄球菌形成松散多孔的生物被膜，这类被膜更易被白细胞浸润并清除。本研究结果表明，非那洛芬是一种具备临床应用潜力的强效抗毒力制剂，且SaeR可作为抗金黄色葡萄球菌植入物相关感染的药物靶点。