Crystallographic analyses of isoquinoline complexes reveal a new mode of metallo-β-lactamase inhibition

What is it about?

Crystallographic analyses of the VIM-5 metallo-β-lactamase (MBL) with isoquinoline inhibitors reveal non zinc ion binding modes. Comparison with other MBL-inhibitor structures directed addition of a zinc-binding thiol enabling identification of potent B1 MBL inhibitors. The inhibitors potentiate meropenem activity against clinical isolates harboring MBLs.

Featured Image

Why is it important?

Crystallographic analyses of the clinically relevant VIM-5 B1 MBL in complex with enantiomeric isoquinolines reveal that although they interact with slightly different regions of the VIM-5 active site, binding of each involves residues on the catalytically important L3 and L10 loops. The combined crystallographic and solution results also reveal an MBL inhibition mode not involving Zn(II) ion chelation. Comparison of structures with recently reported inhibitor-MBL structures led to the design of highly potent, broad-spectrum MBL inhibitors, which were also found to potentiate the efficacy of meropenem against MBL-producing strains. Since these compounds can be readily prepared, they are good starting points for further optimisation.