Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections
文献类型：期刊论文
| 作者 | Jiang, Feng2; Chen, Yingjia1,3; Yu, Jinlong2; Zhang, Feiyang2; Liu, Qian4; He, Lei4; Musha, Hamushan2; Du, Jiafei2; Wang, Boyong2; Han, Pei2 |
| 刊名 | ACS CENTRAL SCIENCE
 |
| 出版日期 | 2023-06-15 |
| 页码 | 20 |
| ISSN号 | 2374-7943 |
| DOI | 10.1021/acscentsci.3c00499 |
| 通讯作者 | Tang, Jin(tangjin6ph@163.com) ; Li, Min(rjlimin@shsmu.edu.cn) ; Shen, Hao(shenhao7212@shsmu.edu.cn) |
| 英文摘要 | Implant-associated infections (IAIs)caused by S. aureus can result in seriouschallenges afterorthopedic surgery. Due to biofilm formation and antibiotic resistance,this refractory infection is highly prevalent, and finding drugs toattenuate bacterial virulence is becoming a rational alternative strategy.In S. aureus, the SaeRS two-componentsystem (TCS) plays a key role in the production of over 20 virulencefactors and the pathogenesis of the bacterium. Here, by conductinga structure-based virtual screening against SaeR, we identified thatfenoprofen, a USA Food and Drug Administration (FDA)-approved nonsteroidanti-inflammatory drug (NSAID), had excellent inhibitory potency againstthe response regulator SaeR protein. We showed that fenoprofen attenuatedthe virulence of S. aureus withoutdrug resistance. In addition, it was helpful in relieving osteolysisand restoring the walking ability of mice in vitro and in implant-associatedinfection models. More importantly, fenoprofen treatment suppressedbiofilm formation and changed the biofilm structure, which caused S. aureus to form loose and porous biofilms thatwere more vulnerable to infiltration and elimination by leukocytes.Our results reveal that fenoprofen is a potent antivirulence agentwith potential value in clinical applications and that SaeR is a drugtarget against S. aureus implant-associatedinfections. Implant-associated infections (IAIs) caused by S.aureus can result in serious challenges after orthopedicsurgery. Due to biofilm formation and antibiotic resistance, thisrefractory infection is highly prevalent, and finding drugs to attenuatebacterial virulence is becoming a rational alternative strategy. In S. aureus, the SaeRS two-component system (TCS) playsa key role in the production of over 20 virulence factors and thepathogenesis of the bacterium. Here, by conducting a structure-basedvirtual screening against SaeR, we identified that fenoprofen, a USAFood and Drug Administration (FDA)-approved nonsteroid anti-inflammatorydrug (NSAID), had excellent inhibitory potency against the responseregulator SaeR protein. We showed that fenoprofen attenuated the virulenceof S. aureus without drug resistance.In addition, it was helpful in relieving osteolysis and restoringthe walking ability of mice in vitro and in implant-associated infectionmodels. More importantly, fenoprofen treatment suppressed biofilmformation and changed the biofilm structure, which caused S. aureus to form loose and porous biofilms thatwere more vulnerable to infiltration and elimination by leukocytes.Our results reveal that fenoprofen is a potent antivirulence agentwith potential value in clinical applications and that SaeR is a drugtarget against S. aureus implant-associatedinfections. |
| WOS关键词 | NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; SIGNAL-TRANSDUCTION ; 2-COMPONENT SYSTEM ; ENDOTHELIAL-CELLS ; EXTRACELLULAR DNA ; GENE-EXPRESSION ; BIOFILMS ; INTERNALIZATION ; OSTEOARTHRITIS ; MECHANISMS |
| 资助项目 | Experimental Animal Research Project of the Shanghai Science and Technology Commission[21140904800] ; National Natural Science Foundation of China[82272511] ; National Natural Science Foundation of China[81974325] ; National Natural Science Foundation of China[81873957] ; National Natural Science Foundation of China[82172325] ; National Natural Science Foundation of China[81974311] ; Medical Guidance Scientific Research Support Project of the Shanghai Science and Technology Commission[19411962600] ; Shanghai Committee of Science and Technology, China[19JC1413005] ; Shanghai Pujiang Program[2019PJD026] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:001011633100001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306316]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Tang, Jin; Li, Min; Shen, Hao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Sch Med, Dept Orthoped, Shanghai 200235, Peoples R China 3.Univ Chinese Acad Sci, Dept Pharm, Beijing 100049, Peoples R China 4.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Lab Med, Shanghai 200127, Peoples R China 5.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Dept Infect Dis, Sch Med, Shanghai 200235, Peoples R China 6.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Sch Med, Dept Clin Lab, Shanghai 200235, Peoples R China 7.Shanghai Jiao Tong Univ, Sch Med, Fac Med Lab Sci, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jiang, Feng,Chen, Yingjia,Yu, Jinlong,et al. Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections[J]. ACS CENTRAL SCIENCE,2023:20. |
| APA | Jiang, Feng.,Chen, Yingjia.,Yu, Jinlong.,Zhang, Feiyang.,Liu, Qian.,...&Shen, Hao.(2023).Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.ACS CENTRAL SCIENCE,20. |
| MLA | Jiang, Feng,et al."Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections".ACS CENTRAL SCIENCE (2023):20. |
入库方式： OAI收割
来源：上海药物研究所
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