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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.

Author information

1
Center for Drug Design & Bioinformatics and Computational Biology, Program, University of Minnesota, Minneapolis, MN, 55455, USA.
2
Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA.
3
Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA.
4
Department of Experimental and Clinical Pharmacology & Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, 55455, USA.
5
Current address: Department of Integrative Biology & University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN, 55455, USA.

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 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.

KEYWORDS:

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

PMID:
28482143
PMCID:
PMC6034706
DOI:
10.1002/cmdc.201700182
[Indexed for MEDLINE]
Free PMC Article

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