Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
Division of Orthopaedic Surgery, University of Western Ontario, London Health Sciences Centre, University Hospital, London, Ontario, Canada.
mSphere. 2021 Mar 10;6(2):e00143-21. doi: 10.1128/mSphere.00143-21.
Osteoarthritis is the most prevalent joint disease in the United States, with many patients requiring surgical replacement of the affected joint. The number of joint arthroplasty procedures performed each year is increasing, and infection is a leading cause of implant failure. is the most frequently isolated organism associated with periprosthetic joint infections of the knee or hip, and due to the emergence of antibiotic-resistant strains, treatment options are limited. Here, we show that synovial fluid from osteoarthritic patients is iron restrictive toward and, for strains representing the clonal lineages USA100, USA200, USA400, and USA600, bactericidal. Remarkably, community-associated methicillin-resistant (CA-MRSA) strain USA300-LAC was highly resistant to synovial fluid killing but could be sensitized to killing by mutation of the GraXRS regulatory system and GraXRS-regulated gene or by small-molecule inhibition of GraR. Thus, we propose the GraXRS-VraFG regulatory system and as targets for future therapeutics for treatment of bone and joint infections. Osteoarthritis, a degenerative disease that results in the breakdown of joint cartilage and underlying bone, is the most prevalent joint disease in the United States. Surgical intervention, including total joint replacement, is a clinically effective procedure that can help to restore the patient's quality of life. Unfortunately, joint replacement procedures come with a risk of infection that is estimated to occur in 1 to 2% of cases, and periprosthetic joint infection (PJI) is a leading cause of implant failure, requiring revision surgery. is well known for its ability to cause PJIs and was found to be the most frequently isolated organism from PJIs of the knee or hip. Antibiotic-resistant strains can often limit treatment options. In this study, we demonstrate that the MRSA strain LAC can resist killing and grow in human synovial fluid from osteoarthritic knees. Furthermore, we show that the GraXRS regulatory system is required for the displayed synovial fluid resistance. We further demonstrate that a small-molecule inhibitor of GraR sensitizes LAC to synovial fluid, validating the Gra system as a therapeutic target for the treatment of PJIs in humans.
骨关节炎是美国最常见的关节疾病，许多患者需要手术更换受影响的关节。每年进行的关节置换手术数量正在增加，感染是植入物失败的主要原因。 是与膝关节或髋关节假体周围关节感染最常相关的分离菌，由于出现抗生素耐药株，治疗选择有限。在这里，我们表明，来自骨关节炎患者的滑液对 和 具有铁限制性，对于代表克隆谱系 USA100、USA200、USA400 和 USA600 的菌株，具有杀菌作用。值得注意的是，社区相关的耐甲氧西林金黄色葡萄球菌（CA-MRSA）菌株 USA300-LAC 对滑液杀伤具有高度抗性，但可以通过突变 GraXRS 调节系统和 GraXRS 调节的 基因或通过小分子抑制 GraR 来敏化杀伤。因此，我们提出 GraXRS-VraFG 调节系统和 作为未来治疗骨和关节感染的治疗靶点。骨关节炎是一种导致关节软骨和下方骨骼分解的退行性疾病，是美国最常见的关节疾病。手术干预，包括全关节置换，是一种临床有效的治疗方法，可以帮助恢复患者的生活质量。不幸的是，关节置换手术存在感染风险，估计在 1%至 2%的病例中发生，假体周围关节感染（PJI）是植入物失败的主要原因，需要进行翻修手术。 因其引起 PJI 的能力而闻名，并且被发现是膝关节或髋关节 PJI 中最常分离的细菌。抗生素耐药株往往会限制治疗选择。在这项研究中，我们证明了 MRSA 菌株 LAC 可以抵抗杀伤并在来自骨关节炎膝关节的人滑液中生长。此外，我们表明 GraXRS 调节系统是显示的滑液抗性所必需的。我们进一步证明了 GraR 的小分子抑制剂使 LAC 对滑液敏感，验证了 Gra 系统作为治疗人类 PJI 的治疗靶点。
