Tanshinone I as a novel therapeutic agent targeting von Willebrand factor-binding protein to mitigate <i>Staphylococcus aureus</i> pathogenicity

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a prevalent pathogen responsible for a wide range of diseases in humans, contributing to both hospital-acquired and community-acquired infections. The von Willebrand factor-binding protein (vWbp) is pivotal for <i>S. aureus</i> pathogenicity because it induces blood coagulation, thereby facilitating bacterial survival and dissemination within the host. Notably, the absence of vWbp does not hinder <i>S. aureus</i> growth, indicating that vWbp is an attractive target for combating <i>S. aureus</i> infections while mitigating the risk of antibiotic resistance. Our findings revealed that tanshinone I significantly inhibited vWbp-induced coagulation without affecting the proliferation of <i>S. aureus</i>. Hemolysis assays confirmed the biocompatibility of tanshinone I, while Western blot analysis, fluorescence quenching, and thermal shift assays (TSAs) demonstrated that tanshinone I does not alter vWbp expression but directly binds to the protein. Molecular docking studies elucidated the interaction mechanism, identifying ARG-479 and GLN-484 as critical residues for tanshinone I binding. Furthermore, <i>in vivo</i> studies demonstrated that tanshinone I reduces lung tissue damage in mice infected with <i>S. aureus</i>, thereby increasing survival rates. Additionally, tanshinone I was tested in greater wax moth larvae and showed similar protective effects. In conclusion, tanshinone I effectively inhibits vWbp, reducing the virulence of <i>S. aureus</i>. This study underscores the potential of tanshinone I as a therapeutic agent against <i>S. aureus</i> infections, offering a novel strategy to combat bacterial infections while decreasing the critical issue of antibiotic resistance.