Discovery of Novel Inhibitor Scaffolds against the Metallo-β-lactamase VIM‑2 by Surface Plasmon Resonance (SPR) Based Fragment Screening

Metallo-β-lactamase (MBL) inhibitors
can restore the function
of carbapenem antibiotics and therefore help to treat infections of
antibiotic resistant bacteria. In this study, we report novel fragments
inhibiting the clinically relevant MBL Verona integron-encoded metallo-β-lactamase
(VIM-2). The fragments were identified from a library of 490 fragments
using an orthogonal screening approach based on a surface plasmon
resonance (SPR) based assay combined with an enzyme inhibition assay.
The identified fragments showed IC50 values between 14
and 1500 μM and ligand efficiencies (LE) between 0.48 and 0.23
kcal/mol per heavy atom. For two of the identified fragments, crystal
structures in complex with VIM-2 were obtained. The identified fragments
represent novel inhibitor scaffolds and are good starting points for
the design of potent MBL inhibitors. Furthermore, the established
SPR based assay and the screening approach can be adapted to other
MBLs and in this way improve the drug discovery process for this important
class of drug targets.