Abstract
Bacterial metallo-β-lactamases (MBLs) are involved in resistance to β-lactam antibiotics including cephalosporins. Human SNM1A and SNM1B are MBL superfamily exonucleases that play a key role in the repair of DNA interstrand cross-links, which are induced by antitumour chemotherapeutics, and are therefore targets for cancer chemosensitization. We report that cephalosporins are competitive inhibitors of SNM1A and SNM1B exonuclease activity; both the intact β-lactam and their hydrolysed products are active. This discovery provides a lead for the development of potent and selective SNM1A and SNM1B inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins
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Cephalosporins / chemical synthesis
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Cephalosporins / chemistry
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Cephalosporins / pharmacology*
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DNA Repair / drug effects*
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DNA Repair Enzymes / antagonists & inhibitors*
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DNA Repair Enzymes / metabolism
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Exodeoxyribonucleases / antagonists & inhibitors*
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Exodeoxyribonucleases / metabolism
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Humans
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Models, Molecular
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Molecular Conformation
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism
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Structure-Activity Relationship
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beta-Lactamases / metabolism*
Substances
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Cell Cycle Proteins
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Cephalosporins
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Enzyme Inhibitors
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Nuclear Proteins
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DCLRE1A protein, human
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DCLRE1B protein, human
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Exodeoxyribonucleases
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beta-Lactamases
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DNA Repair Enzymes