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8hxw

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Crystal structure of B1 VIM-2 MBL in complex with 2-amino-5-heptylthiazole-4-carboxylic acid

Structural highlights

8hxw is a 2 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.39Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q9K2N0_PSEAI

Publication Abstract from PubMed

Metallo-beta-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic beta-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.

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-beta-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.,Yan YH, Zhang TT, Li R, Wang SY, Wei LL, Wang XY, Zhu KR, Li SR, Liang GQ, Yang ZB, Yang LL, Qin S, Li GB J Med Chem. 2023 Oct 12;66(19):13746-13767. doi: 10.1021/acs.jmedchem.3c01189. , Epub 2023 Oct 4. PMID:37791640^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yan YH, Zhang TT, Li R, Wang SY, Wei LL, Wang XY, Zhu KR, Li SR, Liang GQ, Yang ZB, Yang LL, Qin S, Li GB. Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding. J Med Chem. 2023 Oct 12;66(19):13746-13767. PMID:37791640 doi:10.1021/acs.jmedchem.3c01189