Discovery of 2‑Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

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.