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Eur J Med Chem ; 219: 113418, 2021 Jul 05.
Article in English | MEDLINE | ID: mdl-33862516

ABSTRACT

The occurrence of resistances in Gram negative bacteria is steadily increasing to reach extremely worrying levels and one of the main causes of resistance is the massive spread of very efficient ß-lactamases which render most ß-lactam antibiotics useless. Herein, we report the development of a series of imino-analogues of ß-lactams (namely azetidinimines) as efficient non-covalent inhibitors of ß-lactamases. Despite the structural and mechanistic differences between serine-ß-lactamases KPC-2 and OXA-48 and metallo-ß-lactamase NDM-1, all three enzymes can be inhibited at a submicromolar level by compound 7dfm, which can also repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1. We show that 7dfm can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A (KPC-2), B (NDM-1) and D (OXA-48) with Ki's below 0.3 µM, but also the cephalosporinase CMY-2 (class C, 86% inhibition at 10 µM). Our results pave the way for the development of a new structurally original family of non-covalent broad-spectrum inhibitors of ß-lactamases.


Subject(s)
Anti-Bacterial Agents/chemistry , Azetidines/chemistry , beta-Lactamase Inhibitors/chemistry , beta-Lactamases/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Azetidines/metabolism , Binding Sites , Catalytic Domain , Cell Line , Cell Proliferation/drug effects , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Gram-Negative Bacteria/drug effects , Humans , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Docking Simulation , Structure-Activity Relationship , beta-Lactamase Inhibitors/metabolism , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/genetics , beta-Lactamases/metabolism
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