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

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.