Iminodiacetic Acid as a Novel Metal-Binding Pharmacophore for New Delhi Metallo-β-lactamase Inhibitor Development

Abstract

The fungal natural product aspergillomarasmine A (AMA) has been identified as a noncompetitive inhibitor of New Delhi metallo-β-lactamase-1 (NDM-1) that inhibits by removing Zn^II from the active-site. The nonselective metal-chelating properties and 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 use of IDA for fragment-based drug discovery (FBDD) of NDM-1 inhibitors. IDA (IC₅₀ =120 μM) was developed into inhibitor 23 f (IC₅₀ =8.6 μM, K_i =2.6 μM), which formed 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 with inhibitor derivatization, the use of IDA as an alternative AMA scaffold for NDM-1 inhibitor development is detailed.

Keywords: New Delhi metallo-β-lactamase; antibiotic resistance; aspergillomarasmine A; iminodiacetic acid; metal chelator.