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Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo β-Lactamase Inhibitor.
- Source :
-
ChemMedChem [ChemMedChem] 2017 Jun 07; Vol. 12 (11), pp. 845-849. Date of Electronic Publication: 2017 May 22. - Publication Year :
- 2017
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Abstract
- VIM-2 is one of the most common carbapenem-hydrolyzing metallo β-lactamases (MBL) found in many drug-resistant Gram-negative bacterial strains. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in-class metallo β-lactamase inhibitor (MBLi) with a potent inhibition K <subscript>i</subscript> of 13 nm against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency. We further established that 3 can restore the antibiotic activity of amoxicillin against VIM-2-producing E. coli in a whole cell assay with an EC <subscript>50</subscript> of 110 nm. The potential mode of binding of 3 from molecular modeling provided structural insights that could corroborate the observed changes in the biochemical activities. Finally, 3 possesses a low cytotoxicity (CC <subscript>50</subscript> ) of 97 μm with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.<br /> (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Cell Survival drug effects
Escherichia coli drug effects
HEK293 Cells
Humans
Inhibitory Concentration 50
Microbial Sensitivity Tests
Models, Molecular
Picolinic Acids toxicity
Pseudomonas aeruginosa drug effects
Thiones toxicity
beta-Lactamase Inhibitors toxicity
beta-Lactamases metabolism
Picolinic Acids chemical synthesis
Picolinic Acids pharmacology
Thiones chemical synthesis
Thiones pharmacology
beta-Lactamase Inhibitors chemistry
beta-Lactamase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 12
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 28482143
- Full Text :
- https://doi.org/10.1002/cmdc.201700182