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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.

Type

Journal article

Journal

Chemical communications (Cambridge, England)

Publication Date

05/2016

Volume

52

Pages

6727 - 6730

Addresses

Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. peter.mchugh@imm.ox.ac.uk and Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.