Anti-infective therapy of inhibiting Staphylococcus aureus ClpP by protocatechuic aldehyde

The increasing antibiotic resistance and widespread pathogenicity of Staphylococcus aureus (S. aureus) has resulted in severe infections in both human and animals, necessitating the urgent development of novel therapeutic agents. Targeting virulence factors has emerged as a promising approach to combat infections caused by drug-resistant bacteria. Protocatechuic aldehyde (PCA) was identified as an inhibitor of S. aureus ClpP through an enzyme activity inhibition assay. Treatment with PCA at concentrations of 64 and 128 μg/mL significantly reduced the proteolytic and hemolytic activities of S. aureus, as well as its adherence and invasion capabilities. Furthermore, S. aureus treated with PCA exhibited decreased persistence under adverse stress conditions, including elevated temperature, NaClO, and H₂O₂ stress. Furthermore, the bactericidal activity of tigecycline against S. aureus was enhanced when used in combination with PCA. Molecular simulations revealed that PCA directly binded to ClpP at the G107, V88, and I81 residues, thereby further inhibiting its activity. In vivo, PCA treatment improved survival rates and reduced inflammatory responses in a mouse model of S. aureus-induced pneumonia. Overall, PCA represents an effective therapeutic agent against S. aureus infections by inhibiting ClpP activity, providing a novel strategy to combat S. aureus.