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ACS Central Science

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

Published:15 June 2023 DOI: 10.1021/acscentsci.3c00499 PMID: 37521790
Feng Jiang, Yingjia Chen, Jinlong Yu, Feiyang Zhang, Qian Liu, Lei He, Hamushan Musha, Jiafei Du, Boyong Wang, Pei Han, Xiaohua Chen, Jin Tang*, Min Li* and Hao Shen*, 

Abstract

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.

Substances (20)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Ibuprofen 15687-27-1 C13H18O2 1026 suppliers $5.00-$1560.00
Ibuprofen 15687-27-1 C13H18O2 1026 suppliers $5.00-$1560.00
Ibuprofen 15687-27-1 C13H18O2 1026 suppliers $5.00-$1560.00
Ibuprofen 15687-27-1 C13H18O2 1026 suppliers $5.00-$1560.00
Naproxen 22204-53-1 C14H14O3 766 suppliers $8.00-$957.10
Naproxen 22204-53-1 C14H14O3 766 suppliers $8.00-$957.10
Naproxen 22204-53-1 C14H14O3 766 suppliers $8.00-$957.10
Naproxen 22204-53-1 C14H14O3 766 suppliers $8.00-$957.10
Oxaceprol 33996-33-7 C7H11NO4 287 suppliers $39.20-$3011.26
Oxaceprol 33996-33-7 C7H11NO4 287 suppliers $39.20-$3011.26

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