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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.

Original publication

DOI

10.1039/c6cc00529b

Type

Journal article

Journal

Chem Commun (Camb)

Publication Date

10/05/2016

Volume

52

Pages

6727 - 6730

Keywords

Cephalosporins, DNA Repair, DNA Repair Enzymes, Dose-Response Relationship, Drug, Enzyme Inhibitors, Exodeoxyribonucleases, Humans, Models, Molecular, Molecular Conformation, Nuclear Proteins, Structure-Activity Relationship, beta-Lactamases