[en] The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.
Disciplines :
Chemistry
Author, co-author :
Lienard, Benoit M R
Garau, Gianpiero
Horsfall, Louise
Karsisiotis, Andreas I
Damblon, Christian ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique structurale
Lassaux, Patricia ; Université de Liège - ULiège > Centre d'ingénierie des protéines
Papamicael, Cyril
Roberts, Gordon C K
Galleni, Moreno ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Dideberg, Otto
Frère, Jean-Marie ; Université de Liège - ULiège > Centre d'ingénierie des protéines
Schofield, Christopher J
Language :
English
Title :
Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols
Publication date :
2008
Journal title :
Organic and Biomolecular Chemistry
ISSN :
1477-0520
eISSN :
1477-0539
Publisher :
Royal Society of Chemistry, Cambridge, United Kingdom
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
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