Adaptive evolution of the Clf-Sdr subfamily contributes to Staphylococcus aureus musculoskeletal infection: Evidence...

Persistent Staphylococcus aureus infections of the musculoskeletal system are a challenge in clinical practice. Although extensive studies on the genotypic changes in S. aureus in soft tissue and blood system infections have been conducted, little is known about how S. aureus adapts to the microenvironment of the musculoskeletal system. Here, we used comparative genomics to analyze the isolates from patients with an S. aureus infection of the musculoskeletal system. We observed that mutations in the Clf-Sdr subfamily proteins frequently occurred during persistent infections. Furthermore, these mutations were primarily located in the non-active site (R region), rather than in the active site (A region). Mechanistically, the clfA/B mutation enhanced the S. aureus biofilm formation ability through the binding to fibrinogen and intercellular adhesion. Complementation studies using the USA300-ΔMSCRAMMs strains clfA and clfB revealed that mutations in both the A and R regions could enhance their corresponding function. The results of protein structure prediction and ligand-binding simulations suggest that these mutations influence the protein structure and ligand binding. In conclusion, our study suggests that the Clf-Sdr subfamily mutations may be one of the mechanisms contributing to persistent S. aureus infections of the musculoskeletal system.