biostudies-literaturevan Haren MJEuropean Research Council3806-3811https://www.ebi.ac.uk/biostudies/studies/S-EPMC7986777biostudies-literatureUnknown27(11)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 nm 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 Chemistry (Weinheim an der Bergstrasse, Germany)Cephalosporin Prodrug Inhibitors Overcome Metallo-β-Lactamase Driven Antibiotic Resistance.PMC7986777ERC consolidator grant (grant agreement no. 725523)725523Bruchle NCTehrani KHMEWade Nvan Haren MJMartin NIKotsogianni IMashayekhi VfalseCephalosporin Prodrug Inhibitors Overcome Metallo-β-Lactamase Driven Antibiotic Resistance.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 nm 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 2021-01-01T00:00:00Z2021 Feb2025-04-27T01:16:36.204Z2025-02-19T00:35:14.325ZS-EPMC79867773323760410.1002/chem.202004694