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Cephalosporin Prodrug Inhibitors Overcome Metallo‐β‐Lactamase Driven Antibiotic Resistance
Author(s) -
Haren Matthijs J.,
Tehrani Kamaleddin H. M. E.,
Kotsogianni Ioli,
Wade Nicola,
Brüchle Nora C.,
Mashayekhi Vida,
Martin Nathaniel I.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202004694
Subject(s) - dipicolinic acid , prodrug , cephalosporin , meropenem , cephalosporin antibiotic , chemistry , microbiology and biotechnology , antibiotics , antibiotic resistance , biochemistry , biology , spore
The increasing prevalence of metallo‐β‐lactamase (MBL)‐expressing bacteria presents a worrying trend in antibiotic resistance. MBLs rely on active site zinc ions for their hydrolytic activity and the pursuit of MBL‐inhibitors has therefore involved the investigation of zinc chelators. To ensure that such chelators specifically target MBLs, a series of cephalosporin prodrugs of two potent zinc‐binders: dipicolinic acid (DPA) and 8‐thioquinoline (8‐TQ) was prepared. Although both DPA and 8‐TQ bind free zinc very tightly ( K d values in the low n m range), the corresponding cephalosporin conjugates do not. The cephalosporin conjugates are efficiently hydrolyzed by MBLs to release DPA or 8‐TQ, as confirmed by using both NMR and LC‐MS studies. Notably, the cephalosporin prodrugs of DPA and 8‐TQ show potent inhibitory activity against NDM, VIM, and IMP classes of MBLs and display potent synergy with meropenem against MBL‐expressing clinical isolates of K. pneumoniae and E. coli .