ORBi: Lassaux Patricia - Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-ß-lactamases

Reference : Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-ß-lactamases


	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology
	To cite this reference:	http://hdl.handle.net/2268/93545

Title :	Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-ß-lactamases
Language :	English
Alternative title :	[fr] Composés mercaptophosphonates en tant qu'inhibiteurs à large spectre de métallo-ß-lactamases
Author, co-author :	Lassaux, Patricia [ > > ]
	Hamel, Matthieu [ > > ]
	Gulea, Mihaela [ > > ]
	Delbrück, Heinrich [ > > ]
	Mercuri, Paola [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
	Horsfall, Louise [ > > ]
	Dehareng, Dominique [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
	Kupper, Michaël [ > > ]
	Frère, Jean-Marie [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
	Hoffmann, Kurt [ > > ]
	Galleni, Moreno [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >]
	Bebrone, Carine [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Publication date :	2010
Journal title :	Journal of Medicinal Chemistry
Publisher :	American Chemical Society
Volume :	53
Pages :	4862–4876
Audience :	International
ISSN :	0022-2623
e-ISSN :	1520-4804
City :	Washington
Country :	DC
Keywords :	[en] Metallo-ß-lactamases ; inhibitors ; mercaptophosphonate
Abstract :	[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. 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. 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.
Funders :	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 ; European Regional Development Fund (ERDF) ; Loterie Nationale (Lot. Nat. 9.4538.03)
Target :	Researchers ; Professionals
Permalink :	http://hdl.handle.net/2268/93545
DOI :	10.1021/jm100213c

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