Iminodiacetic Acid as a Novel Metal-binding Pharmacophore for New Delhi Metallo-b-lactamase Inhibitor Development .

The fungal natural product Aspergillomarasmine A (AMA) has been identified as a non-competitive inhibitor of New Delhi Metallo-β-lactamase-1 (NDM-1) that inhibits via active site Zn(II) removal.  The non-selective metal-chelating properties and the difficult synthesis and derivatization of AMA have hindered the development of this scaffold into a potent and selective inhibitor of NDM-1.  Iminodiacetic acid ( IDA ) has been identified as the metal-binding pharmacophore (MBP) core of AMA that can be leveraged for inhibitor development.  Herein, we report the utilization of  IDA  for the fragment-based drug discovery (FBDD) of NDM-1 inhibitors.   IDA  (IC50 = 122 μM) was developed into inhibitor  23f  (IC50 = 8.6 μM,  K i = 2.6 μM) and displayed the formation of a ternary complex with NDM-1, as evidenced by protein thermal shift and native state electrospray ionization mass spectrometry (ESI-MS) experiments.  Combining mechanistic analysis in tandem with inhibitor derivatization, the potential for utilizing the  IDA  NDM-1 inhibitor development is detailed. .