Fig. 1: Design and synthesis of the dynamically chiral phosphonic acid-based metallo-β-lactamase inhibitors.

a Our inhibitor design (circled) makes use of prior knowledge of the mechanism of β-lactam hydrolysis and of structural features of existing β-lactam antibiotics and β-lactamase inhibitors. b Synthetic route towards the stereodynamic phosphonic acid inhibitors 5a–m, which were designed to act as adaptive inhibitors of bacterial metallo-β-lactamase enzymes. This route provides straightforward variability of the moiety R connected via an amide bond. The acidity of the benzylic proton is responsible for the stereochemical dynamics. The phenyl (h) and benzyl (m) analogues are included to assess whether a sulfurous motif is beneficial for binding.