Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1

Kamal Tehrani, Haigen Fu, Nora Bruchle, Vida Mashayekhi, Alejandro Prats Lujan, Matthijs Van Haren, Gerrit J Poelarends, Nathaniel I. Martin*

*Corresponding author for this work

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Abstract

A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-β-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.

Original languageEnglish
Pages (from-to)3047-3049
Number of pages4
JournalChemical Communications
Volume56
Issue number20
Early online date5-Feb-2020
DOIs
Publication statusPublished - 2020

Keywords

  • ASYMMETRIC-SYNTHESIS

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