Anti-glucosaminidase monoclonal antibodies as a passive immunization for methicillin-resistant Staphylococcus aureus (MRSA) orthopedic infections

Abstract

Recently, methicillin-resistant Staphylococcus aureus (MRSA) has surpassed HIV as the most deadly pathogen in the United States, accounting for over 100,000 deaths per year. In orthopedics, MRSA osteomyelitis has become the greatest concern in patient care, despite the fact that improvements in surgical technique and aggressive antibiotic prophylaxis have decreased the infection rate for most procedures to less than 5%. This great concern is largely due to the very poor outcomes associated with MRSA osteomyelitis, which includes 30-50% failure rates for revision surgery. Thus, there is a need to develop additional therapeutic interventions such as passive immunization, particularly for immunocompromised patients and the elderly who are typically poor responders to active vaccines. Using a novel murine model of implant-associated osteomyelitis in which a stainless steel pin is coated with bioluminescent S. aureus and implanted transcortically through the tibial metaphysis, we discovered that mice protect themselves from this infection by mounting a specific IgG2b response against the peptidoglycan hydrolase, glucosaminidase (Gmd), an enzyme involved in cell wall digestion during binary fission. Since this subunit of S. aureus autolysin is essential for bacterial growth, and no genetic variation has been identified among clinical strains, we propose that monoclonal antibodies against this enzyme would have multiple mechanisms of action, including promotion of opsonophagocytosis and direct inhibition of enzyme function. Here we review the field of MRSA osteomyelitis and our research to date on the development of an anti-Gmd passive immunotherapy.