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ChemMedChem. 2017 Jun 7;12(11):845-849. doi: 10.1002/cmdc.201700182. Epub 2017 May 22.

Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo β-Lactamase Inhibitor.

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Center for Drug Design & Bioinformatics and Computational Biology, Program, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA.
Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA.
Department of Experimental and Clinical Pharmacology & Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, 55455, USA.
Current address: Department of Integrative Biology & University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN, 55455, USA.


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 Ki 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 EC50 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 (CC50 ) of 97 μm with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.


1-hydroxypyridine-2(1H)-thiones; VIM-2; drug resistance; metallo β-lactamase; pyrithiones; β-lactam antibiotics

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