8HXE
Crystal structure of B3 L1 MBL in complex with 2-amino-5-(4-propylbenzyl)thiazole-4-carboxylic acid
Summary for 8HXE
| Entry DOI | 10.2210/pdb8hxe/pdb |
| Descriptor | Metallo-beta-lactamase L1 type 3, ZINC ION, 2-azanyl-5-[(4-propylphenyl)methyl]-1,3-thiazole-4-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | beta-lactamase class b l1, hydrolase |
| Biological source | Stenotrophomonas maltophilia (Pseudomonas maltophilia, Xanthomonas maltophilia) |
| Total number of polymer chains | 2 |
| Total formula weight | 57812.71 |
| Authors | |
| Primary citation | 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 Cited by 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: 37791640DOI: 10.1021/acs.jmedchem.3c01189 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.382 Å) |
Structure validation
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