Plasminogen Recruitment by Staphylococcus aureus SdrC Reveals a Tractable Antivirulence Target

Staphylococcus aureus exploits host extracellular matrix components to promote tissue invasion and dissemination. Here, we identify the serine-aspartate repeat protein C (SdrC) as a previously unrecognized plasminogen-binding protein on the S. aureus surface. Using recombinant domains and isogenic mutants, we show that SdrC is a major determinant of plasminogen recruitment at the cellular level. Biochemical and biophysical analyses demonstrate that plasminogen recognition is enhanced by the cooperative action of the SdrC N2 and N3 domains, which together bind plasminogen with submicromolar to low-micromolar affinity. This interaction is lysine-dependent and is selectively inhibited by lysine and 6-aminocaproic acid, with measurable IC50 values, and requires plasminogen kringle domain 4. Importantly, SdrC-bound plasminogen remains readily activatable by host plasminogen activators, generating active plasmin capable of degrading fibrinogen. Consistently, heterologous expression of SdrC enhances plasminogen binding and promotes plasmin activity at the bacterial surface. These findings link a defined staphylococcal adhesin to localized engagement of the host fibrinolytic system and suggest that SdrC-mediated plasminogen recruitment may contribute to persistence and tissue dissemination during invasive infection. Overall, our results establish the SdrC-plasminogen axis as a mechanistically characterized and pharmacologically tractable antivirulence target.