| Autor: |
Yan, Yu-Hang, Zhang, Ting-Ting, Li, Rong, Wang, Si-Yao, Wei, Liu-Liu, Wang, Xin-Yue, Zhu, Kai-Rong, Li, Shan-Rui, Liang, Guo-Qing, Yang, Zeng-Bao, Yang, Ling-Ling, Qin, Shangshang, Li, Guo-Bo |
| Zdroj: |
Journal of Medicinal Chemistry; October 2023, Vol. 66 Issue: 19 p13746-13767, 22p |
| Abstrakt: |
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. |
| Databáze: |
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