Mechanistic investigations of metallo- β-lactamase inhibitors: Strong zinc binding is not required for potent enzyme inhibition.

Mechanistic investigations of metallo-β-lactamase inhibitors: Strong zinc binding is not required for potent enzyme inhibition. ChemMedChem. 2021 Feb 03;: Authors: Wade N, Tehrani K, Brüchle N, van Haren M, Mashayekhi V, Martin NI Abstract Metallo-β-lactamases (MBLs) are zinc-dependent bacterial enzymes that inactivate essentially all classes of β-lactam antibiotics, including last resort carbapenems. At present there are no clinically approved MBL inhibitors and in order to develop such agents it is essential to understand their inhibitory mechanisms. We here describe a comprehensive mechanistic study on a panel of structurally distinct MBL inhibitors reported in both the scientific and patent literature. Specifically, we determined the half-maximal inhibitory concentration (IC50) for each inhibitor against MBLs belonging to the NDM and IMP families. In addition, the binding affinities of the inhibitors for Zn2+, Ca2+ and Mg2+ were assessed using isothermal titration calorimetry (ITC). We also compared the ability of the different inhibitors to resensitize a highly resistant MBL-expressing E. coli strain to meropenem. These investigations reveal clear differences between the MBL inhibitors with both in terms of their IC50 values, metal binding abilities, and capacity to synergize with meropenem. Notably, our studies reveal that potent MBL inhibition and synergy with meropenem is not explicitly dependent on the capacity of an inh...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research