The in vitro and in vivo potential of metal-chelating agents as metallo-beta-lactamase inhibitors against carbapenem-resistant Enterobacterales. Issue 1 (15th December 2022)

• Record Type: Journal Article
• Authors: Omolabi, Kehinde F; Reddy, Nakita; Mdanda, Sipho; Ntshangase, Sphamandla; Singh, Sanil D; Kruger, Hendrik G; Naicker, Tricia; Govender, Thavendran; Bajinath, Sooraj
• Is Part Of: FEMS microbiology letters. Volume 370:Issue 1(2023)
• Publication Date: 2022-12-15
• Subjects: NOTA -- carbapenem-resistant Enterobacterales -- infection modeling -- combination therapy; Microbiology -- Periodicals; 579
• DOI: 10.1093/femsle/fnac122
• Languages: English
• ISSNs: 0378-1097

Abstract

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. Abstract : An investigation into the potential activity of metal chelators as novel therapeutics for the treatment of carbapenem-resistant infections.