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

Abstract 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 vitr...

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Published in:FEMS microbiology letters 2023-01, Vol.370
Main Authors: Omolabi, Kehinde F, Reddy, Nakita, Mdanda, Sipho, Ntshangase, Sphamandla, Singh, Sanil D, Kruger, Hendrik G, Naicker, Tricia, Govender, Thavendran, Bajinath, Sooraj
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - pharmacology
Bacteria
beta-Lactamase Inhibitors - pharmacology
beta-Lactamases
Carbapenems - pharmacology
Chelating agents
Chelating Agents - pharmacology
Chelation
Effectiveness
In vivo methods and tests
Inhibitors
Klebsiella
Meropenem
Meropenem - pharmacology
Metallo-β-lactamase
Metallography
Mice
Microbial Sensitivity Tests
Pharmacokinetics
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Summary:Abstract 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 log10 units). The findings suggest that chelators, such as NOTA, hold strong potential for use as a MBL inhibitor in treating carbapenem-resistant Enterobacterale infections. An investigation into the potential activity of metal chelators as novel therapeutics for the treatment of carbapenem-resistant infections.
ISSN:1574-6968
0378-1097
1574-6968
DOI:10.1093/femsle/fnac122