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

项目摘要 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）是全膝关节置换术后最严重的并发症，也是全膝关节置换术后最大的并发症， 关节置换翻修约占所有翻修的25%。PJI的5年死亡率为20%，高于大多数 癌的噬菌体治疗是一种很有前途的治疗慢性细菌感染的方法。我们小组已经完成了 在FDA的同情使用指南下，一系列噬菌体疗法用于治疗顽固性慢性PJI病例。 基于其成功，这是一项独立资助的FDA II/III期研究， 开始.这些疗法利用噬菌体、细菌特异性病毒来结合和裂解细菌。 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噬菌体 与临床分离株相匹配该方法类似于使用CLSI方案确定抗生素敏感性。 将噬菌体与分离物匹配是必要的，因为噬菌体结合特异性表面受体， 同一种细菌的变异。在PJI中最常见的微生物金黄色葡萄球菌中， 主要与壁磷壁酸（WTA）（一种肽聚糖受体）结合。WTA可以具有不同的糖基化 这取决于细菌的局部环境和生长状态。这项建议的目的是 确定WTA糖基化的变化如何在不同的环境条件下变化，以及它们的结果 对噬菌体活性的影响。这将有助于我们制定PJI新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允许准确的 噬菌体选择，从而产生有效的可重复的方案，为未来的临床研究提供信息， 疗法

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.