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 inhibitor was evaluated in combination with meropenem against metallo-beta-lactamase 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 co-administration of NOTA and meropenem (100 mg/kg.bw each) resulted in a significant decrease in the colony-forming units of K. pneumoniae NDM-1 over an eight-hour treatment period (> 3 log10 units). The findings suggest that chelators, such as NOTA, hold strong potential for use as a metallo-beta-lactamase inhibitor in treating carbapenem-resistant Enterobacterale infections.