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.
MeSH terms
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Aspartic Acid / analogs & derivatives*
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Aspartic Acid / chemistry
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Aspartic Acid / pharmacology
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Coordination Complexes / chemical synthesis
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Coordination Complexes / chemistry
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Coordination Complexes / pharmacology*
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Dose-Response Relationship, Drug
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Escherichia coli Proteins / antagonists & inhibitors*
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Escherichia coli Proteins / metabolism
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Ethylenediamines / chemistry
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Ethylenediamines / pharmacology*
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Molecular Structure
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Structure-Activity Relationship
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Succinates / chemistry
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Succinates / pharmacology*
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Zinc / chemistry
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Zinc / pharmacology*
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beta-Lactamase Inhibitors / chemical synthesis
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beta-Lactamase Inhibitors / chemistry
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beta-Lactamase Inhibitors / pharmacology*
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beta-Lactamases / metabolism
Substances
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Amino Acids
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Coordination Complexes
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Escherichia coli Proteins
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Ethylenediamines
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Succinates
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beta-Lactamase Inhibitors
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N,N'-ethylenediamine disuccinic acid
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Aspartic Acid
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aspergillomarasmine A
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NDM-1 protein, E coli
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beta-Lactamases
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Zinc