Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo.
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.
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.
Sook Y
SY
Lee
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Jürgen
J
Brem
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Ilaria
I
Pettinati
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Timothy D W
TD
Claridge
Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, OX3 7DQ, UK.
Opher
O
Gileadi
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Christopher J
CJ
Schofield
Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. peter.mchugh@imm.ox.ac.uk.
Peter J
PJ
McHugh
D018797:Cell Cycle Proteins; D002511:Cephalosporins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C115339:DCLRE1A protein, human; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D001618:beta-Lactamases; D045643:DNA Repair Enzymes