Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.
Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.
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DOI：
10.1021/acscentsci.3c00499
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发表时间：
2023-07-26
影响因子：
18.2
通讯作者：
Shen, Hao
中科院分区：
文献类型：
--
作者：
Jiang, Feng;Chen, Yingjia;Yu, Jinlong;Zhang, Feiyang;Liu, Qian;He, Lei;Musha, Hamushan;Du, Jiafei;Wang, Boyong;Han, Pei;Chen, Xiaohua;Tang, Jin;Li, Min;Shen, Hao
由金黄色葡萄球菌引起的种植体相关感染（IAIs）可导致骨科手术后的严重挑战。由于生物膜的形成和抗生素耐药性，这种难治性感染非常普遍，寻找药物来减弱细菌的毒力正成为一种合理的替代策略。在金黄色葡萄球菌中，SaeRS双组分系统（TCS）在20多种毒力因子的产生和细菌的发病机制中起关键作用。在这里，通过对SaeR进行基于结构的虚拟筛选，我们发现非诺洛芬，美国食品和药物管理局（FDA）批准的非甾体抗炎药（NSAID），对反应调节因子SaeR蛋白具有出色的抑制效力。我们发现，非诺洛芬可以减轻金黄色葡萄球菌的毒力，但不产生耐药性。此外，在体外和植入物相关感染模型中，它有助于缓解骨溶解和恢复小鼠的行走能力。更重要的是，非诺洛芬抑制了生物膜的形成，改变了生物膜的结构，使金黄色葡萄球菌形成疏松多孔的生物膜，更容易被白细胞浸润和清除。我们的研究结果表明，非诺洛芬是一种有效的抗毒剂，具有潜在的临床应用价值，SaeR是一种抗金黄色葡萄球菌植入物相关感染的药物靶点。由金黄色葡萄球菌引起的种植体相关感染（IAIs）可导致骨科手术后的严重挑战。由于生物膜的形成和抗生素耐药性，这种难治性感染非常普遍，寻找药物来减弱细菌的毒力正成为一种合理的替代策略。在金黄色葡萄球菌中，SaeRS双组分系统（TCS）在20多种毒力因子的产生和细菌的发病机制中起关键作用。在这里，通过对SaeR进行基于结构的虚拟筛选，我们发现非诺洛芬，美国食品和药物管理局（FDA）批准的非甾体抗炎药（NSAID），对反应调节因子SaeR蛋白具有出色的抑制效力。我们发现，非诺洛芬可以减轻金黄色葡萄球菌的毒力，但不产生耐药性。此外，在体外和植入物相关感染模型中，它有助于缓解骨溶解和恢复小鼠的行走能力。更重要的是，非诺洛芬抑制了生物膜的形成，改变了生物膜的结构，使金黄色葡萄球菌形成疏松多孔的生物膜，更容易被白细胞浸润和清除。我们的研究结果表明，非诺洛芬是一种有效的抗毒剂，具有潜在的临床应用价值，SaeR是一种抗金黄色葡萄球菌植入物相关感染的药物靶点。
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. 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.
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