Isoalantolactone Enhances the Antimicrobial Activity of Penicillin G against Staphylococcus aureus by Inactivating β-Lactamase during Protein Translation

Abstract

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 β-lactamase-positive S. aureus.

Back to the Roots—An Overview of the Chemical Composition and Bioactivity of Selected Root-Essential Oils

“…Furthermore, it could recently be shown that IAL synergistically increased the antimicrobial effects of penicillin G against S. aureus by inactivating β-lactamase. Thus, a therapy of combined IAL and penicillin G demonstrated equal effects compared with sulbactam with penicillin G [ 184 ]. These findings suggested that IAL—in combination with β-lactam antibiotics—may be a promising drug in the treatment of S. aureus pneumonia [ 183 , 184 ].…”

“…Thus, a therapy of combined IAL and penicillin G demonstrated equal effects compared with sulbactam with penicillin G [ 184 ]. These findings suggested that IAL—in combination with β-lactam antibiotics—may be a promising drug in the treatment of S. aureus pneumonia [ 183 , 184 ]. Furthermore, it could be shown that low micromolecular concentrations (1–20 µM) of ALT intensified the uptake of S. aureus and thus stimulated immune functions of macrophages [ 185 ].…”

Characterization of Corosolic Acid as a KPC-2 Inhibitor That Increases the Susceptibility of KPC-2-Positive Bacteria to Carbapenems

“…The β-lactamase activity was detected using nitrocefin as described previously ( Zhou et al., 2020 ). In this study, it was first determined that CA inhibited the activity of KPC-2 during bacterial growth and in unprocessed culture supernatants.…”

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“…Isoalantolactone showed synergistic effects against 21 β-lactamase-positive S. aureus strains (including methicillin-resistant S. aureus , when combining with penicillin G). The association of drugs was also effective on S. aureus -infected mice, increasing the survival rate (88.24%) after 144 h treatment [ 87 ].…”