Diclofenac Resensitizes Methicillin‐Resistant Staphylococcus aureus to β‐Lactams and Prevents Implant Infections

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.