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 ZnII 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, Ki=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.

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

“…More recently, iminodiacetic acid was employed by Cohen and Crowder as a scaffold for obtaining more potent NDM-1 inhibitors. The best compound inhibited NDM-1 by binding instead of stripping the metal ions with low-μM affinity . A series of benzimidazole and benzoxazole-based compounds reported by the Franz group resulted in sub-μM inhibitory potency through binding rather than chelation .…”

Dual-Function Potentiation by PEG-BPEI Restores Activity of Carbapenems and Penicillins against Carbapenem-Resistant Enterobacteriaceae

“…The NDM-1 enzyme requires Zn 2+ ions for activity. − Overcoming carbapenem resistance by disabling MBLs with Zn 2+ chelators is well-known. ,,− Other strategies overcome resistance by targeting MBLs with inhibitors. ,− Compounds that bind to the LPS layer to facilitate the influx of antibacterial agents are often designed from peptide or peptidomimetic scaffolds, ,,, although resistance has developed . These well-founded and important developments highlight the utility of single-function compounds that inhibit carbapenemases, inhibit efflux pumps, increase the uptake of these inhibitors and various antibiotics, or chelate and sequester Zn 2+ ions essential for MBLs.…”

Elusive structural changes of New Delhi metallo-β-lactamase revealed by ultraviolet photodissociation mass spectrometry

“…This observation is consistent with other studies that show a general increase in overall thermostability of NDM-1 upon binding inhibitors. 45 More specically, our use of native UVPD-MS reveals that fragmentation of the backbone spanning the ASL1 region shows the greatest suppression, specically bracketing the residue F70, which is positioned at the apex of this substrate-binding beta-hairpin loop (Fig. 3).…”

“…Native MS has previously been used to detect changes in the metalation state of NDM-1 upon inhibitor binding. 42,45 Here we apply UVPD-MS and an established Zn2 ejector to more extensively elucidate structural changes that occur throughout the NDM-1 protein upon inhibitor binding. The non-selective thiol reagent ebselen (3) has been examined as a ligand for a wide variety of cysteine-containing proteins by using mass spectrometry.…”