| Summary: | Abstract Implant infections caused by methicillin‐resistant Staphylococcus aureus (MRSA) can cause major complications during the perioperative period. Diclofenac, one of the most widely used nonsteroidal anti‐inflammatory drugs, is often used to relieve pain and inflammation. In this study, it is found that high‐dose diclofenac can inhibit the growth of MRSA, and does not easily induce drug‐resistant mutations after continuous passage. However, low‐doses diclofenac can resensitize bacteria to β‐lactams, which help to circumvent drug resistance and improve the antibacterial efficacy of conventional antibiotics. Further, low‐dose diclofenac in combination with β‐lactams inhibit MRSA associated biofilm formation in implants. Transcriptomic and proteomic analyses indicate that diclofenac can reduce the expression of genes and proteins associated with β‐lactam resistance: mecA, mecR, and blaZ; peptidoglycan biosynthesis: murA, murC, femA, and femB; and biofilm formation: altE and fnbP. Murine implant infection models indicate that diclofenac combined with β‐lactams, can substantially alleviate MRSA infections in vivo. In addition, it is investigated that low dose diclofenac can inhibit MRSA antibiotic resistance via the mecA/blaZ pathway and related biofilms in implants. The synergistic effect of diclofenac and β‐lactams might have promising applications for preventing perioperative infection, considering its multitarget effects against MRSA.
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