New polyimidazole ligands against subclass B1 metallo-β-lactamases: Kinetic, microbiological, docking analysis

Beta-lactam antibiotics are one of the most commonly used drug classes in managing bacterial infections. However, their use is threatened by the alarming phenomenon of antimicrobial resistance, which represents a worldwide health concern. Given the continuous spread of metallo-8-lactamases (MBLs) producing pathogens, the need to discover broad-spectrum 8-lactamase inhibitors is increasingly growing. A series of zinc chelators have been synthesized and investigated for their ability to hamper the Zn-ion network of interactions in the active site of MBLs. We assessed the inhibitory activity of new polyimidazole ligands N,N '-bis((imidazol-4-yl) methyl)-ethylenediamine, N,N,N '-tris((imidazol-4-yl)methyl)-ethylenediamine, N,N,N,N '-tetra((imidazol-4-yl-methyl)-ethylenediamine toward three different subclasses B1 MBLs: VIM-1, NDM-1 and IMP-1 by in vitro assays. The activity of known zinc chelators such as 1,4,7,10,13-Pentaazacyclopentadecane, 1,4,8,11-Tetraazacyclote-tradecane and 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid was also assessed. Moreover, a molec-ular docking study was carried to gain insight into the interaction mode of the most active ligands.