Diclofenac Resensitizes Methicillin-Resistant Staphylococcus aureus to β-Lactams and Prevents Implant Infections.
Diclofenac Resensitizes Methicillin-Resistant Staphylococcus aureus to β-Lactams and Prevents Implant Infections.
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DOI：
10.1002/advs.202100681
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Yue B
中科院分区：
文献类型：
--
作者：
Zhang S;Qu X;Tang H;Wang Y;Yang H;Yuan W;Yue B
耐甲氧西林金黄色葡萄球菌（MRSA）引起的植入物感染可导致围手术期的主要并发症。双氯芬酸是应用最广泛的非甾体类抗炎药之一，常用于缓解疼痛和炎症。本研究发现，大剂量双氯芬酸可以抑制MRSA的生长，并且在连续传代后不易诱导耐药突变。然而，低剂量双氯芬酸可以使细菌对β -内酰胺重新敏感，这有助于避免耐药性并提高常规抗生素的抗菌效果。此外，低剂量双氯芬酸联合β内酰胺可抑制植入物中MRSA相关生物膜的形成。转录组学和蛋白质组学分析表明，双氯芬酸可以降低与β -内酰胺耐药相关的基因和蛋白质的表达：mecA、mecR和blaZ；肽聚糖生物合成：murA、murC、femA和femB；和生物膜形成：altE和fnbP。小鼠植入物感染模型表明，双氯芬酸联合β -内酰胺类药物可显著减轻体内MRSA感染。此外，还研究了低剂量双氯芬酸可通过植入物中的mecA/blaZ途径及相关生物膜抑制MRSA抗生素耐药性。双氯芬酸和β内酰胺的协同作用可能在预防围手术期感染方面有很好的应用，考虑到其对MRSA的多靶点作用。双氯芬酸增强耐甲氧西林金黄色葡萄球菌对β -内酰胺类抗生素的敏感性，有助于规避耐药，提高常规抗生素的抗菌效果。此外，小鼠植入物感染模型显示双氯芬酸联合奥西林可减轻MRSA感染。机制研究表明双氯芬酸可通过MecA/BlaZ途径抑制MRSA抗生素耐药性。
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. Diclofenac enhances the sensitivity of methicillin‐resistant Staphylococcus aureus toward the β‐lactam antibiotics, which help to circumvent drug resistance and improve the antibacterial efficacy of conventional antibiotics. Besides, murine implant infection models show that diclofenac combined with oxacillin, can alleviate MRSA infections. Mechanistic studies indicate that diclofenac can inhibit MRSA antibiotic resistance through the MecA/BlaZ pathway.
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