Fluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding pose

Abstract

Bacterial resistance to the majority of clinically used β-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-β-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding. The new compounds showed activity comparable to the non-fluorinated inhibitors against the New Delhi Metallo-β-lactamase-1 (NDM-1). The most active compound, a derivative of D-captopril, exhibited an IC₅₀ value of 0.3 μM. Several compounds demonstrated synergistic effects, restoring the effect of meropenem and reducing the minimum inhibitory concentration (MIC) values in NDM-1 (up to 64-fold), VIM-2 (up to 8-fold) and IMP-26 (up to 8-fold) harbouring Escherichia coli. NMR spectroscopy and molecular docking of one representative inhibitor determined the binding pose in NDM-1, demonstrating that fluorinated analogues of inhibitors are a valuable tool for structural studies of MBL-inhibitor complexes.

Keywords: IMP-26; Inhibitors; Metallo-β-lactamases; NDM-1; NMR binding-studies; Thiols; VIM-2.