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

Abstract
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.
AuthorsYu-Hang Yan, Ting-Ting Zhang, Rong Li, Si-Yao Wang, Liu-Liu Wei, Xin-Yue Wang, Kai-Rong Zhu, Shan-Rui Li, Guo-Qing Liang, Zeng-Bao Yang, Ling-Ling Yang, Shangshang Qin, Guo-Bo Li
JournalJournal of medicinal chemistry (J Med Chem) Vol. 66 Issue 19 Pg. 13746-13767 (10 12 2023) ISSN: 1520-4804 [Electronic] United States
PMID37791640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • beta-Lactamase Inhibitors
  • Carbapenems
  • Meropenem
  • 2-aminothiazole
  • Carboxylic Acids
  • beta-Lactamases
  • Anti-Bacterial Agents
Topics
  • Animals
  • Mice
  • beta-Lactamase Inhibitors (pharmacology, chemistry)
  • Carbapenems (pharmacology)
  • Meropenem (pharmacology)
  • Carboxylic Acids
  • beta-Lactamases (metabolism)
  • Anti-Bacterial Agents (pharmacology, chemistry)

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