The Role of Teichoic Acid Glycosylation in Phage Activity and Selection in an Ongoing FDA Phase II/III Clinical Study of Bacteriophage Therapy in Chronic Periprosthetic Joint Infection

FDA 正在进行的一项噬菌体治疗慢性假体周围关节感染的 II/III 期临床研究中，磷壁酸糖基化在噬菌体活性和选择中的作用

• 批准号: 10704149
• 负责人: James B. Doub
• 金额: $ 41.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704149
• 关键词: Address; Antibiotics; Bacteria; Bacterial Infections; Bacteriophages; Binding; Biological Assay; Bioreactors; Case Series; Chronic; Clinical; Clinical Research; Complication; Culture Media; Data; Effectiveness; Enrollment; Environment; FDA approved; Failure; Funding; Future; Goals; Growth; Guidelines; Histologic; Implant; In Vitro; Knowledge; Libraries; Malignant Neoplasms; Measures; Methods; Microbial Biofilms; Operative Surgical Procedures; Organism; Outcome; Pathway interactions; Patient Isolation; Patients; Pattern; Periprosthetic joint infection; Phase; Phenotype; Population; Process; Protocols documentation; Reproducibility; Role; Safety; Series; Site; Staphylococcus aureus; Surface; Synovial Fluid; Teichoic Acids; Testing; Therapeutic; Tissues; Treatment Protocols; United States; Variant; Virus; Work; bone; glycosylation; improved; in vitro activity; in vivo; knee replacement arthroplasty; mortality; novel strategies; novel therapeutic intervention; novel therapeutics; peptidoglycan receptor; receptor; screening; soft tissue; success; tissue culture; Address; Antibiotics; Bacteria; Bacterial Infections; Bacteriophages; Binding; Biological Assay; Bioreactors; Case Series; Chronic; Clinical; Clinical Research; Complication; Culture Media; Data; Effectiveness; Enrollment; Environment; FDA approved; Failure; Funding; Future; Goals; Growth; Guidelines; Histologic; Implant; In Vitro; Knowledge; Libraries; Malignant Neoplasms; Measures; Methods; Microbial Biofilms; Operative Surgical Procedures; Organism; Outcome; Pathway interactions; Patient Isolation; Patients; Pattern; Periprosthetic joint infection; Phase; Phenotype; Population; Process; Protocols documentation; Reproducibility; Role; Safety; Series; Site; Staphylococcus aureus; Surface; Synovial Fluid; Teichoic Acids; Testing; Therapeutic; Tissues; Treatment Protocols; United States; Variant; Virus; Work; bone; glycosylation; improved; in vitro activity; in vivo; knee replacement arthroplasty; mortality; novel strategies; novel therapeutic intervention; novel therapeutics; peptidoglycan receptor; receptor; screening; soft tissue; success; tissue culture

PROJECT SUMMARY The most common major surgical procedure in the United States is total knee arthroplasty. Periprosthetic joint infection (PJI) is the most severe complication in total knee arthroplasty, and the largest reason for total knee arthroplasty revision in approximately 25% of all revisions. The 5-year mortality for PJI is 20%, higher than most cancers. Bacteriophage therapy is a promising therapy for chronic bacterial infections. Our group has completed a series of phage therapies in recalcitrant chronic PJI cases under compassionate use guidelines with the FDA. Based on its success, this is now an independently funded FDA Phase II/III study where enrollment has just begun. These therapies utilize bacteriophages, viruses specific to bacteria, to bind and lyse the bacteria. Preoperative bacterial cultures are obtained and screened against a large phage library to select a specific phage matched to the clinical isolate. This method is similar to determining antibiotic sensitivity using CLSI protocols. Matching a phage to an isolate is necessary as phages bind specific surface receptors that can have large variations in the same bacterial species. In Staphylococcus aureus, the most common organism in PJI, phages primarily bind to wall teichoic acid (WTA), a peptidoglycan receptor. WTA can have different glycosylation dependent on the local environment and growth states of the bacteria. The objective of this proposal is to determine how changes in WTA glycosylation vary under different environmental conditions and their resulting impact on phage activity. This will contribute to our long-term goal to develop new treatment strategies for PJI. The rationale for this work is that an improved understanding of changes in WTA glycosylation will allow accurate phage selection to consequently create effective reproducible protocols to inform future clinical studies and therapy.

项目摘要 美国最常见的主要手术程序是全膝关节置换术。人假体关节 感染（PJI）是总膝关节置换术中最严重的并发症，也是总膝盖的最大原因 关节置换术在所有修订的大约25％中进行修订。 PJI的5年死亡率为20％，高于大多数 癌症。噬菌体治疗是一种有希望的慢性细菌感染疗法。我们的小组已经完成 在FDA的富有同情心使用指南下，顽固慢性PJI病例中的一系列噬菌体疗法。 基于其成功，这是一项由独立资助的FDA II/III研究 开始。这些疗法利用细菌特异性病毒的噬菌体结合和裂解细菌。 获得术前细菌培养物，并针对大噬菌体文库进行筛选以选择特定的噬菌体 与临床分离株匹配。该方法类似于使用CLSI方案确定抗生素敏感性。 将噬菌体与分离物相匹配是必要的，因为噬菌体结合了特定的表面受体 同一细菌物种的变化。在金黄色葡萄球菌中，PJI中最常见的生物，噬菌体 主要与肽聚糖受体结合壁teichoic酸（WTA）。 WTA可以具有不同的糖基化 取决于细菌的局部环境和生长状态。该提议的目的是 确定WTA糖基化的变化在不同的环境条件下如何变化 对噬菌体活动的影响。这将有助于我们为PJI制定新的治疗策略的长期目标。 这项工作的理由是，对WTA糖基化变化的变化有了改进的理解将允许准确 噬菌体选择以创建有效的可重复方案，以告知未来的临床研究和 治疗。