The in vitro and in vivo potential of metal-chelating agents as metallo-beta-lactamase inhibitors against carbapenem-resistant Enterobacterales

The recent surge in beta-lactamase resistance has created superbugs, which pose a current and significant threat to public healthcare. This has created an urgent need to keep pace with the discovery of inhibitors that can inactivate these beta-lactamase producers. In this study, the in vitro and in vivo activity of 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA)-a potential metallo-beta-lactamase (MBL) inhibitor was evaluated in combination with meropenem against MBL producing bacteria. Time-kill studies showed that NOTA restored the efficacy of meropenem against all bacterial strains tested. A murine infection model was then used to study the in vivo pharmacokinetics and efficacy of this metal chelator. The coadministration of NOTA and meropenem (100 mg/kg.bw each) resulted in a significant decrease in the colony-forming units of Klebsiella pneumoniae NDM-1 over an 8-h treatment period (> 3 log(10) units). The findings suggest that chelators, such as NOTA, hold strong potential for use as a MBL inhibitor in treating carbapenem-resistant Enterobacterale infections.

Automated summary

The recent surge in beta-lactamase resistance has led to the emergence of superbugs, posing a significant threat to public healthcare. This study evaluated the potential of 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA) as a metallo-beta-lactamase (MBL) inhibitor in combination with meropenem against MBL producing bacteria. The results showed that NOTA restored the efficacy of meropenem and significantly decreased the colony-forming units of carbapenem-resistant Klebsiella pneumoniae in a murine infection model.