Isoalantolactone Enhances the Antimicrobial Activity of Penicillin G againstby Inactivatingβ-lactamase during Protein Translation.
Pathogens. 2020 Feb 26 ;9(3). Epub 2020 Feb 26. PMID: 32110983
β-Lactamase-positiveis 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 21β-lactamase-positivestrains (including methicillin resistant). 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 differentβ-lactamases or β-lactamase-positivestrains, in vitro, to confirm the mechanism of inhibition ofβ-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-positivewere less than 0.5, and ranged from 0.10± 0.02 to 0.38 ± 0.17. The survival rate of-infected mice increased significantly from 35.29% to 88.24% within 144 h following multiple compound therapy approaches. Unlike sulbactam, IAL inactivatedβ-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.