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 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.

In Vitro and In Vivo Development of a β-Lactam-Metallo-β-Lactamase Inhibitor: Targeting Carbapenem-Resistant Enterobacterales

“…Our research group has previously demonstrated that metal chelating agents, like NOTA, DOTA, and DPA, are potent MBL inhibitors, acting on MBL-producing CREs. , These compounds exhibited undetectable toxic effects at effective concentrations in vitro . However, the highly polar nature of the isolated chelators made detection in plasma impossible, and they are likely rapidly excreted through renal clearance.…”

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors

“…Potent chelators would be expected to show off-target effects within the biological environment, thus limiting the therapeutic use of simple zinc binders [ 1 ]. Our previous studies indicated that cyclic amino acidic zinc chelators based on contrast agent NOTA exhibit very good β-lactamase inhibition and surprisingly little toxicity; however, the polar nature of NOTA came with pharmacokinetic challenges [ 37 , 38 , 39 ]. Hence, we envisaged that conjugation of the chelator to a known drug would enhance its properties.…”

Synthesis and biological evaluation of novel β-lactam-metallo β-lactamase inhibitors

“…17,33 Our group recently investigated the antibacterial effect of cyclic amino acidic zinc chelators when co-administered with the clinically-used carbapenem antibiotics, meropenem and imipenem (the most widely prescribed carbapenem antibiotics worldwide). 12,34,35 We found that conjugation to existing b-lactam antibiotic scaffolds improved the transport of the chelators to the MBL active site, as well as their pharmacokinetics/ pharmacodynamics (PK/PD) prole. 36,37 Our rationale was based on the premise that the chelating moiety would be responsible for MBL inhibition whilst the b-lactam scaffold would provide for increased lipophilicity and selective transport to the bacteria.…”