Diclofenac Resensitizes Methicillin-Resistant Staphylococcus aureus to beta-Lactams and Prevents Implant Infections

Adv Sci (Weinh). 2021 May 3;8(13):2100681. doi: 10.1002/advs.202100681. eCollection 2021 Jul.

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.

PMID:34258168 | PMC:PMC8261494 | DOI:10.1002/advs.202100681