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Abstract :
[en] Metallo-b-lactamases (MBL) represent an emerging problem
due to their capacity to hydrolyze almost all b-lactam antibiotics,
including last generation cephalosporins and carbapenems. Due to the
presence of two chelating functions (sulfanyl and phosphonato), the mercaptophosphonic acids (phosphorous analogues of mercaptocarboxylic acids) are potential candidates for MBL inhibitors.
Methods: The inhibitory effect of 14 mercapto-phosphonate derivatives
against representatives of the three subclasses of MBLs (VIM-4 (B1),
CphA (B2) and L1 (B3)) was previously reported [1]. Here, in order to determine the interactions mediating the positioning of the inhibitors
in the active site of each enzyme, crystallographic and docking studies
were performed with 10a and 18, both inhibitors being active against the
three subclasses.
Results: The crystallographic structure of the CphA-10a and CphA-18
indicated that the sulphur atom of 10a and the phosphonato group of
18 interact with the zinc ion respectively. Molecular modelling on the
VIM-4 (B1) and FEZ-1 (B3) enzymes with 10a and 18 also brought to
light different binding modes depending on the enzyme and the inhibitor,
consistent with the crystallographic structures.
Conclusions: The investigation of mercapto-phosphonate derivatives
as MBL inhibitor has allowed us to find potent inhibitors active on
representative members of all the three MBL subclasses. Moreover, on
the basis of structural and modelling data, the inhibitory strength of these
compounds will be improved further.
Reference(s)
[1] Lassaux P., Hamel M., Gulea M., Mercuri P., Horsfall L.,
Bebrone C., Gaumont A-C., Frère J., Galleni M. Mercaptophosphonate
compounds as broad-spectrum inhibitors of the metallob-
lactamases, Abstract number: 1732_295, ECSMID 2007.
