Abstract
Clavulanate is used as an effective drug in combination with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we perform combined quantum mechanics/molecular mechanics simulations of several covalent complexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-1) from less effective inhibition (KPC-2).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Clavulanic Acid / chemistry
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Clavulanic Acid / pharmacology*
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Escherichia coli / chemistry
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Escherichia coli / drug effects
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Escherichia coli / enzymology*
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Escherichia coli / metabolism
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Escherichia coli Infections / drug therapy
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Escherichia coli Infections / microbiology
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Humans
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Klebsiella Infections / drug therapy
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Klebsiella Infections / microbiology
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Klebsiella pneumoniae / chemistry
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Klebsiella pneumoniae / drug effects
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Klebsiella pneumoniae / enzymology*
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Klebsiella pneumoniae / metabolism
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Thermodynamics
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beta-Lactamase Inhibitors / chemistry
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beta-Lactamase Inhibitors / pharmacology*
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beta-Lactamases / chemistry
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beta-Lactamases / metabolism*
Substances
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beta-Lactamase Inhibitors
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Clavulanic Acid
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beta-lactamase KPC-2
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beta-Lactamases
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beta-lactamase TEM-1