Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

Nat Chem. 2014 Dec;6(12):1084-90. doi: 10.1038/nchem.2110. Epub 2014 Nov 17.


The use of β-lactam antibiotics is compromised by resistance, which is provided by β-lactamases belonging to both metallo (MBL)- and serine (SBL)-β-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in β-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including (19)F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biophysics
  • Crystallography
  • Hydrolysis
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Meropenem
  • Rhodanine / chemistry*
  • Rhodanine / pharmacology
  • Thienamycins / pharmacology
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / chemistry


  • Thienamycins
  • beta-Lactamase Inhibitors
  • Rhodanine
  • beta-Lactamases
  • Meropenem

Associated data

  • PubChem-Substance/221675618
  • PubChem-Substance/221675619