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.
Original language | English (US) |
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Pages (from-to) | 845-849 |
Number of pages | 5 |
Journal | ChemMedChem |
Volume | 12 |
Issue number | 11 |
DOIs | |
State | Published - Jun 7 2017 |
Bibliographical note
Publisher Copyright:© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Keywords
- 1-hydroxypyridine-2(1H)-thiones
- VIM-2
- drug resistance
- metallo β-lactamase
- pyrithiones
- β-lactam antibiotics