Article (Scientific journals)
Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases
Lassaux, Patricia; Hamel, Matthieu; Gulea, Mihaela et al.
2010In Journal of Medicinal Chemistry, 53, p. 4862–4876
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Keywords :
mercaptophosphonate; inhibitors; Metallo-ß-lactamases
Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lassaux, Patricia ;  Université de Liège - ULiège > 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 ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Horsfall, Louise;  Université de Liège - ULiège > Centre d'Ingénierie des Protéines
Dehareng, Dominique ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Kupper, Michaël;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH
Frère, Jean-Marie ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Hoffmann, Kurt;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH
Galleni, Moreno ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Bebrone, Carine ;  Université de Liège - ULiège > Centre d'Ingénierie des Protéines
Language :
English
Title :
Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases
Alternative titles :
[fr] Composés mercaptophosphonates en tant qu'inhibiteurs à large spectre de métallo-ß-lactamases
Publication date :
2010
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
53
Pages :
4862–4876
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
BELSPO - Service Public Fédéral de Programmation Politique scientifique [BE]
FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture [BE]
Loterie Nationale [BE]
Interuniversity Attraction Poles
Gouvernement Fédéral Belge [BE]
FEDER - Fonds Européen de Développement Régional [BE]
Funding number :
Loterie Nationale (Lot. Nat. 9.4538.03)
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