Targeting catabolite control protein A in Staphylococcus aureus with auranofin†

The emergence of antibiotic-resistant Staphylococcus aureus poses a huge threat to public health. Therefore, novel strategies to overcome antibiotic resistance are urgently needed. Auranofin, a marketed metallodrug for rheumatoid arthritis, has been recognized as a promising agent against multiple clinical isolates of S. aureus. However, its antibacterial mechanism is not yet well understood. Herein, we verified that the catabolite control protein A (CcpA) in S. aureus is an important target of auranofin. Auranofin was found to directly bind to CcpA via two cysteine residues. Importantly, both in vitro and animal infection model assays demonstrated that auranofin could disrupt the biological activity of CcpA, which attenuated bacterial growth, inhibited toxin secretion and enhanced the efficacy of aminoglycoside antibiotic. Together, these findings further revealed the bactericidal mechanism of auranofin against S. aureus.