New I2-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-I2-lactamases

In an effort to test whether a transition state analog is an inhibitor of the metallo-I2-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 100 mu M. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities.