Metallo-β-lactamases (MBLs) are
zinc-dependent
enzymes capable of hydrolyzing all bicyclic β-
lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with
carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic
acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of
carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-
carbapenem product complexes. AtCs restored
Meropenem activity against MBL-producing isolates. In the murine
sepsis model, AtCs exhibited favorable synergistic efficacy with
Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential
drug candidates to combat MBL-mediated antimicrobial resistance.