Binding of 2-(Triazolylthio)acetamides to Metallo-β-lactamase CcrA Determined with NMR.

Metallo-β-lactamase (MBL)-producing bacteria resistant to β-lactam antibiotics are a serious threat to human health. Despite great efforts and important progress in the discovery of MBL inhibitors (MBLIs), there is none in clinical use. Herein, inhibitor complexes of the MBL CcrA were investigated by NMR spectroscopy to provide perspectives on the further development of 2-(triazolylthio)acetamide-type MBLIs.

The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor.

The increasing number of pathogens expressing metallo-β-lactamases (MBLs), and in this way achieving resistance to β-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with β-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified.

Azolylthioacetamide: A Highly Promising Scaffold for the Development of Metallo-β-lactamase Inhibitors.

A new scaffold, azolylthioacetamide, was constructed and assayed against metallo-β-lactamases (MβLs). The obtained molecules specifically inhibited MβL ImiS, and 1c was found to be the most potent inhibitor, with a K i = 1.2 μM using imipenem as substrate.

New β-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-β-lactamases.

In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100μM. The phospholactam 1 activated ImiS and BcII at the same concentration.