CcpA promotes Staphylococcus aureus virulence by directly controlling staphyloxanthin production

Staphylococcus aureus is a notorious opportunistic pathogen with remarkable adaptability, enabling it to infect virtually every human tissue. Staphyloxanthin (STX), a critical virulence factor, contributes to S. aureus 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. ccpA deletion considerably reduced STX yield in S. aureus strains with diverse genetic lineages. Western blot showed that CcpA inactivation did not alter SigB expression levels in S. aureus. Gene reporter and electrophoretic mobility shift assays revealed the direct control of CcpA on the expression of the crtOPQMN 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 S. aureus virulence. Notably, inhibition of CcpA with Ag⁺ synergized with vancomycin to combat vancomycin-intermediate S. aureus 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 S. aureus infections.