Oleanolic acid derivative bardoxolone combats multidrug-resistant Staphylococcus aureus by destroying cell membrane and pyruvate metabolism pathway

Abstract Introduction Staphylococcus aureus poses a significant threat to human health, making it imperative to develop novel antimicrobial agents to combat infections caused by this pathogen. Objectives To evaluate the antibacterial efficacy and elucidate the mechanism of bardoxolone as a potential agent against multidrug-resistant S. aureus. Methods Natural products and their derivatives were systematically evaluated for antibacterial activity. The antibacterial activity of bardoxolone was assessed in vitro against planktonic bacteria, internalized bacteria and biofilm-forming multidrug-resistant S. aureus, as well as in vivo using mouse pneumonia and thigh abscess infection models. The underlying antibacterial mechanisms were investigated through quantitative proteomics and a series of biochemical assays. Results Bardoxolone exhibited potent antibacterial efficacy against S. aureus and other Gram-positive pathogens. It demonstrated strong antibacterial activity against internalized and biofilm-associated multidrug-resistant S. aureus, showing low resistance potential. In murine infection models, treatment significantly enhanced survival rates while reducing bacterial burden and attenuating inflammatory responses in pulmonary and femoral tissues. Mechanistic analyses revealed dual antibacterial actions: membrane integrity disruption and suppression of pyruvate metabolism, manifesting as diminished activity of pivotal enzymes, reduced acetyl-CoA/ATP synthesis and consequent growth inhibition of S. aureus. Conclusions These findings suggest that bardoxolone holds promise as a candidate drug for treating refractory multidrug-resistant S. aureus infections.