The rapid spread of β-lactamase-producing bacteria in clinical practice has increasingly deteriorated the performance of β-lactam antibiotics against such resistant strains. Thus, novel agents or strategies for the war against β-lactamase-producing bacteria, especially hypervirulent resistant bacteria (such as toxin-secreting Staphylococcus aureus) carrying complex β-lactamases, are urgently needed. In this study, we found that the natural compound oleanolic acid (OA) and its analogues (especially corosolic acid (CA)) significantly inhibited the activity of important β-lactamases (NDM-1, KPC-2, and VIM-1) in Enterobacteriaceae and β-lactamases (β-lactamase N1) in S. aureus. The results showed significant synergy with β-lactams against β-lactamase-positive bacteria (fractional inhibitory concentration (FIC) index <0.5). Additionally, OA treatment significantly inhibited the activity of hemolysin from various bacteria. In the mouse infection models, the combined therapy with OA and β-lactams exhibited a significant synergistic effect in the treatment of β-lactamase-producing bacteria, as evidenced by the survival rate of S. aureus- or Escherichia coli-infected mice, which increased from 25.0 to 75.0% or from 44.4 to 61.1% (CA increased to 77.8%), respectively, compared to treatment with individual β-lactams. Although OA treatment alone led to systemic protection against S. aureus-infected mice by directly targeting α-hemolysin (Hla), a relatively better therapeutic effect was observed for the combined therapy. To the best of our knowledge, this study is the first to find effective inhibitors against resistant bacterial infections with a two-pronged strategy by simultaneously targeting resistance enzymes and toxins, which may provide a promising therapeutic strategy for drug-resistant bacterial infections.
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