CcpA promotes <i>Staphylococcus aureus</i> virulence by directly controlling staphyloxanthin production

<i>Staphylococcus aureus</i> is a notorious opportunistic pathogen with remarkable adaptability, enabling it to infect virtually every human tissue. Staphyloxanthin (STX), a critical virulence factor, contributes to <i>S. aureus</i> oxidative damage. However, the regulatory mechanism of STX production is incompletely understood. This study provides mechanistic insights into the role of catabolite control protein A (CcpA) in STX production. <i>ccpA</i> deletion considerably reduced STX yield in <i>S. aureus</i> strains with diverse genetic lineages. Western blot showed that CcpA inactivation did not alter SigB expression levels in <i>S. aureus</i>. Gene reporter and electrophoretic mobility shift assays revealed the direct control of CcpA on the expression of the <i>crtOPQMN</i> operon, which encodes enzymes for step-wise STX biosynthesis. Moreover, CcpA deficiency remarkably impaired bacterial tolerance to H₂O₂-mediated killing, decreased survival in whole-blood treatment, and diminished persistence in macrophages. In mouse bacteremia and skin abscess models, CcpA was shown to enhance <i>S. aureus</i> virulence. Notably, inhibition of CcpA with Ag⁺ synergized with vancomycin to combat vancomycin-intermediate <i>S. aureus</i> infections in vivo. Our findings establish CcpA as a SigB-independent regulator of STX production, suggesting that targeting CcpA could be a promising antibiotic synergistic strategy for the management of multidrug-resistant <i>S. aureus</i> infections.