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

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.

项目总结 在美国最常见的主要外科手术是全膝关节置换术。假体周围关节 感染(PJI)是全膝关节置换术中最严重的并发症，也是导致全膝关节置换的最大原因。 关节置换翻修术占所有翻修术的约25%。PJI的5年死亡率为20%，高于大多数 癌症。噬菌体疗法是治疗慢性细菌感染的一种很有前途的疗法。我们小组已经完成了 根据FDA的同情性使用指南对顽固性慢性PJI病例进行的一系列噬菌体疗法。 基于其成功，这现在是一项独立资助的FDA第二/第三阶段研究，在该研究中，登记人数刚刚 开始了。这些疗法利用噬菌体--细菌特有的病毒--来结合和溶解细菌。 手术前获得细菌培养物，并与大噬菌体文库进行筛选，以选择特定的噬菌体 与临床分离株相匹配。这种方法类似于使用CLSI协议来确定抗生素敏感性。 将噬菌体与分离株进行匹配是必要的，因为噬菌体结合了特定的表面受体，这种受体可能具有 同一细菌种类的变异。在金黄色葡萄球菌中，PJI中最常见的有机体是噬菌体 主要与壁磷壁酸(WTA)结合，这是一种肽聚糖受体。WTA可以有不同的糖基化 取决于当地的环境和细菌的生长状态。这项建议的目的是 确定WTA糖基化在不同环境条件下的变化及其结果 对噬菌体活性的影响。这将有助于我们开发新的PJI治疗策略的长期目标。 这项工作的基本原理是，对WTA糖基化变化的更好理解将使准确 噬菌体选择，从而创建有效的可重复的方案，以通知未来的临床研究和 心理治疗。

项目成果

The stability of Staphylococcal bacteriophages with commonly used prosthetic joint infection lavage solutions.

葡萄球菌噬菌体与常用假体关节感染灌洗液的稳定性。

• DOI: 10.1002/jor.25731
• 发表时间: 2024
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Doub,JamesB;Fogel,Jessa;Urish,KenL
• 通讯作者: Urish,KenL