Journal
CHEMMEDCHEM
Volume 12, Issue 12, Pages 972-985Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700186
Keywords
antibiotics; bacterial resistance; lactams; metalloenzymes; nitrogen heterocycles
Categories
Funding
- Agence Nationale de la Recherche (ANTIMBL) [ANR-14-CE16-0028-01]
- Deutsche Forschungsgemeinschaft [BE1540/15-2 within SPP 1710]
- Agence Nationale de la Recherche [ANR-06-BLAN-0086]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE16-0028, ANR-06-BLAN-0086] Funding Source: Agence Nationale de la Recherche (ANR)
Ask authors/readers for more resources
Metallo-beta-lactamases (MBLs) cause resistance of Gram-negative bacteria to beta-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3D structures suggested that the triazolethione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 mm range.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available