β-Lactamase-positive Staphylococcus aureus is one of the most prevalent multidrug-resistant pathogens worldwide and is associated with increasing threats to clinical
therapeutics and public health. Here, we showed that
isoalantolactone (IAL), in combination with
penicillin G, exhibited significant synergism against 21 β-lactamase-positive S. aureus strains (including methicillin resistant S. aureus). An
enzyme inhibition assay, a checkerboard minimum inhibitory concentration (MIC) assay, a growth curve assay, a time-killing assay, a RT-PCR assay and Circular Dichroism (CD) spectroscopy were performed on different β-lactamases or β-lactamase-positive S. aureus strains, in vitro, to confirm the mechanism of inhibition of β-lactamase and the synergistic effects of the combination of
penicillin G and IAL. All the fractional inhibitory concentration (FIC) indices of
penicillin G, in combination with IAL, against β-lactamase-positive S. aureus, were less than 0.5, and ranged from 0.10 ± 0.02 to 0.38 ± 0.17. The survival rate of S. aureus-infected mice increased significantly from 35.29% to 88.24% within 144 h following multiple compound
therapy approaches. Unlike
sulbactam, IAL inactivated β-lactamase during protein translation, and the
therapeutic effect of combination
therapy with IAL and
penicillin G was equivalent to that of
sulbactam with
penicillin G. Collectively, our results indicated that IAL is a promising and leading
drug that can be used to restore the antibacterial effect of β-
lactam antibiotics such as
penicillin G and to address the inevitable
infection caused by βlactamase-positive S. aureus.