Reference : Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/93545
Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases
English
[fr] Composés mercaptophosphonates en tant qu'inhibiteurs à large spectre de métallo-ß-lactamases
Lassaux, Patricia [Université de Liège - ULg > > Centre d'Ingénierie des Protéines > >]
Hamel, Matthieu [Université de Caen Basse-Normandie > > ENSICAEN > >]
Gulea, Mihaela [Université de Caen Basse-Normandie > > ENSICAEN > >]
Delbrück, Heinrich [Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > > > >]
Mercuri, Paola mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Horsfall, Louise [ulg > > Centre d'Ingénierie des Protéines > >]
Dehareng, Dominique [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Kupper, Michaël [Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > > > >]
Frère, Jean-Marie [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Hoffmann, Kurt [Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > > > >]
Galleni, Moreno [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >]
Bebrone, Carine mailto [Université de Liège - ULg > > Centre d'Ingénierie des Protéines > >]
2010
Journal of Medicinal Chemistry
American Chemical Society
53
4862–4876
Yes
International
0022-2623
1520-4804
Washington
DC
[en] mercaptophosphonate ; inhibitors ; Metallo-ß-lactamases
[en] Although commercialized inhibitors of active site serine beta-lactamases are currently used in coadministration with antibiotic therapy, no clinically useful inhibitors of metallo-beta-lactamases (MBLs) have yet been discovered. In this paper, we investigated the inhibitory effect of mercaptophosphonate derivatives against the three subclasses of MBLs (B1, B2, and B3). All 14 tested mercaptophosphonates, with the exception of 1a, behaved as competitive inhibitors for the three subclasses. Apart from 13 and 21, all the mercaptophosphonates tested exhibit a good inhibitory effect on the subclass B2 MBL CphA with low inhibition constants (K(i) < 15 muM). Interestingly, compound 18 turned out to be a potent broad spectrum MBL inhibitor. The crystallographic structures of the CphA-10a and CphA-18 complexes indicated that the sulfur atom of 10a and the phosphonato group of 18 interact with the Zn(2+) ion, respectively. Molecular modeling studies of the interactions between compounds 10a and 18 and the VIM-4 (B1), CphA (B2), and FEZ-1 (B3) enzymes brought to light different binding modes depending on the enzyme and the inhibitor, consistent with the crystallographic structures.
[en] In this paper, we investigated the inhibitory effect of mercaptophosphonate derivatives against the three subclasses of MBLs (B1, B2, and B3). All 14 tested mercaptophosphonates, with the exception of one, behaved as competitive inhibitors for the three subclasses.
<br />Apart from two compounds, all the mercaptophosphonates tested exhibit a good inhibitory effect on the subclass B2 MBL CphA with low inhibition constants (Ki<15 μM). Interestingly, compound 18 turned out to be a potent broad spectrum MBL inhibitor.
<br />The crystallographic structures of the CphA-10a and CphA-18 complexes indicated that the sulfur atom of 10a and the phosphonato group of 18 interact with the Zn2þ ion, respectively. Molecular modeling studies of the interactions between two compounds and the VIM-4 (B1), CphA (B2), and FEZ-1 (B3) enzymes brought to light different binding modes depending on the enzyme and the inhibitor, consistent with the crystallographic structures.
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS ; Politique Scientifique Fédérale (Belgique) = Belgian Federal Science Policy ; Fonds pour la formation à la Recherche dans l'Industrie et dans l'Agriculture (Communauté française de Belgique) - FRIA ; Loterie Nationale (Lot. Nat. 9.4538.03) ; Interuniversity Attraction Poles ; Belgian Federal Government ; European Regional Development Fund
Professionals ; Researchers
http://hdl.handle.net/2268/93545
also: http://hdl.handle.net/2268/143788
10.1021/jm100213c
http://pubs.acs.org/doi/abs/10.1021/jm100213c

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