Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-β-lactamases

Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936. doi: 10.1016/j.bmc.2018.02.043. Epub 2018 Feb 23.


Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

Keywords: Antibiotic resistance; Carbapenemase; Inhibitors; Metallo β-lactamase; Structure activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enediynes / chemistry
  • Inhibitory Concentration 50
  • Molecular Structure
  • Rhodanine / chemical synthesis
  • Rhodanine / chemistry*
  • Rhodanine / pharmacology
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemistry*
  • Sulfhydryl Compounds / pharmacology
  • beta-Lactamase Inhibitors / chemical synthesis*
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamases / chemistry*
  • beta-Lactamases / drug effects


  • Enediynes
  • Sulfhydryl Compounds
  • beta-Lactamase Inhibitors
  • Rhodanine
  • beta-Lactamases