The in vitro inhibitory activity of polypyridine ligands towards subclass B1 metallo-β-lactamases

Abstract

Antimicrobial resistance leads to the ineffectiveness of antimicrobials, hampering the ability to cure infections. Zinc-dependent metallo ß-lactamases (MBLs) producing bacteria represent a threat to public health due to limited therapeutic options. Zinc chelators are able to inhibit MBLs and have the potential to restore carbapenem susceptibility. Recently, polypyridine ligands named Bispicen (N,N’-Bis(2-pyridymethyl)-ethylenediamine), Trispicen (N,N,N’-Tris(2-pyridylmethyl)-ethylenediamine), TrispicenA (N,N,N’-tris([2-pyridylmethyl)-ethylenediamine-N’-acetic acid) and TrispicenDALA (N,N,N’-tris([2-pyridylmethyl)-ethylenediamine-N’-acetyl-D-alanyl-D-alanyl-D-alanine methyl ester) were evaluated for their ability to interfere with the Zn-ion network by interactions in the binding site of MBLs. We report on the inhibitory activity of these ligands towards three subclass B1 MBLs (NDM-1, VIM-1 and IMP-1) by kinetic analysis, demonstrating that all compounds, except TrispicenDALA, acted as competitive inhibitors towards NDM-1 and VIM-1. Bispicen was more active against VIM-1 with Ki value of 0.13 μM while NDM-1 was highly inhibited by Trispicen with Ki value of 0.08 μM. The IMP-1 enzyme was resistant to these compounds showing Ki and IC50 values higher than 500 μM. Docking study reveals that all compounds interact with residues of the MBL active site mainly by the formation of pi-interactions and chelation of both Zn ions. Polypyridine ligands deserve attention for their inhibitory potential towards NDM-1 and VIM-1.