Simvastatin Administration Prohibits Staphylococcus aureus Anti-ROS Adaptation In Vivo and Alleviates Bone Infections

Bone infections in diabetic patients often result in devastating outcomes, highlighting the need for effective treatment strategies. Our study aims to explore how Staphylococcus aureus adapts to the diabetic microenvironment. This study found increased bacterial resistance to reactive oxygen species (ROS) and a higher expression of the crtOPQMN operon among strains isolated from diabetic patients. Mechanistically, S. aureus was found to increase its staphyloxanthin (STX) level through genomic changes in the locus of rsbU, rsbW, and sigB. Both in vitro and in vivo experiments demonstrated that genomic changes were due to bacterial adaptation to the ROS pressure. Moreover, by adopting simvastatin, a representative STX synthesis inhibitor, we found that statins can inhibit the frequency of S. aureus genomic changes under the pressure of ROS. A mouse infection model demonstrated that simvastatin can reduce bacterial loads, alleviate bone infection outcomes, and increase the cure rate of vancomycin in treating bone infections. These findings suggest that by inhibiting bacterial adaptation toward ROS pressure, simvastatins could be a promising adjunctive therapy for bone infection treatment, especially among diabetic patients.