Spectroscopic and biochemical characterization of metallo-8-lactamase IMP-1 with dicarboxylic, sulfonyl, and thiol inhibitors

In an effort to probe the biophysical mechanisms of inhibition for ten previously-reported inhibitors of metallo beta-lactamases (MBL) with MBL IMP-1, equilibrium dialysis, metal analyses coupled with atomic absorption spectroscopy (AAS), native state mass spectrometry (native MS), and ultraviolet-visible spectrophotometry (UVVIS) were used. 6-(1H-tetrazol-5-yl) picolinic acid (1T5PA), ANT431, D/L-captopril, thiorphan, and tiopronin were shown to form IMP-1/Zn(II)/inhibitor ternary complexes, while dipicolinic acid (DPA) and 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid (3AP-DPA) stripped some metal from the active site of IMP but also formed ternary complexes. DPA and 3AP-DPA stripped less metal from IMP-1 than from VIM-2 but stripped more metal from IMP-1 than from NDM-1. In contrast to a previous report, pterostilbene does not appear to bind to IMP-1 under our conditions. These results, along with previous studies, demonstrate similar mechanisms of inhibition toward different MBLs for different MBL inhibitors.

Automated summary

The study demonstrates similar inhibitory mechanisms of different metallo beta-lactamase inhibitors towards different metallo beta-lactamases.