Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo

Chem Commun (Camb). 2016 May 10;52(40):6727-30. doi: 10.1039/c6cc00529b.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Cephalosporins / chemical synthesis
  • Cephalosporins / chemistry
  • Cephalosporins / pharmacology*
  • DNA Repair / drug effects*
  • DNA Repair Enzymes / antagonists & inhibitors*
  • DNA Repair Enzymes / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Exodeoxyribonucleases / antagonists & inhibitors*
  • Exodeoxyribonucleases / metabolism
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Structure-Activity Relationship
  • beta-Lactamases / metabolism*

Substances

  • Cell Cycle Proteins
  • Cephalosporins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • DCLRE1A protein, human
  • DCLRE1B protein, human
  • Exodeoxyribonucleases
  • beta-Lactamases
  • DNA Repair Enzymes