8HY1

Crystal structure of B1 VIM-2 MBL in complex with 2-amino-5-(thiophen-2-ylmethyl)thiazole-4-carboxylic acid

8HY1 の概要

• エントリーDOI: 10.2210/pdb8hy1/pdb
• 分子名称: Beta-lactamase class B VIM-2, ZINC ION, 2-azanyl-5-(thiophen-2-ylmethyl)-1,3-thiazole-4-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: beta-lactamase class b vim-2, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50101.12

構造登録者

Yan, Y.-H.,Zhu, K.-R.,Li, G.-B. (登録日: 2023-01-05, 公開日: 2023-11-01)

主引用文献

Yan, Y.H.,Zhang, T.T.,Li, R.,Wang, S.Y.,Wei, L.L.,Wang, X.Y.,Zhu, K.R.,Li, S.R.,Liang, G.Q.,Yang, Z.B.,Yang, L.L.,Qin, S.,Li, G.B.
Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-beta-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.
J.Med.Chem., 66:13746-13767, 2023

PubMed 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.

PubMed: 37791640
DOI: 10.1021/acs.jmedchem.3c01189

実験手法

X-RAY DIFFRACTION (1.937 Å)