Antibody-antibiotic conjugate targeted therapy for orthopedic implant-associated intracellular S. aureus infections

Abstract

Abstract Background The treatment of orthopedic implant-associated infections, especially those caused by S. aureus, is extremely difficult. The ability of S. aureus to enter cells provides a means for it to evade antibiotics and immune responses during infection, and explains the clinical failure after antibiotic treatment. Therefore, it is critical to identify the host cell type of implant-associated intracellular S. aureus infections and to develop a strategy for highly targeted delivery of antibiotics to the host cells.Methods We introduced an antibody-antibiotic conjugate (AAC) for targeted elimination of intracellular S. aureus. The antibody component of AAC consisted of A human monoclonal antibody (M0662) against the surface antigen Staphylococcal protein A (SpA) of S. aureus. This antibody and vancomycin are conjugated by a cathepsin-sensitive linker, which cleaves in the proteolytic environment of intracellular phagolysosomes, thereby allowing vancomycin to perform its bactericidal action. We then tested the effect of AAC on intracellular S. aureus clearance by in vitro cell experiments and a mice implant infection model.Results In the implant infection model, AAC significantly improved the bactericidal effect of vancomycin. Scanning electron microscopy showed that the application of AAC effectively blocked the formation of bacterial biofilm without obvious toxicity to the host. Further histochemical and micro-CT analysis showed that AAC effectively reversed the imbalance between osteoblasts and osteoclasts and reduced bone loss around the knee joint under infection.Conclusions The application of AAC can effectively avoid the infection spread and recurrence caused by Staphylococcus aureus intracellular infection, which has the application prospect of clinical treatment of orthopedic implant infection.