| Autor: |
Petrella, Stephanie, Ziental-Gelus, Nathalie, Mayer, Claudine, Renard, Murielle, Jarlier, Vincent, Sougakoff, Wladimir |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; October 2008, Vol. 52 Issue: 10 p3725-3736, 12p |
| Abstrakt: |
ABSTRACTTwo clinical strains of Escherichia coli(2138) and Enterobacter cloacae(7506) isolated from the same patient in France and showing resistance to extended-spectrum cephalosporins and low susceptibility to imipenem were investigated. Both strains harbored the plasmid-contained blaTEM-1and blaKPC-2genes. blaKLUC-2, encoding a mutant of the chromosomal β-lactamase of Kluyvera cryocrescens, was also identified at a plasmid location in E. cloacae7506, suggesting the ISEcp1-assisted escape of blaKLUCfrom the chromosome. Determination of the KPC-2 structure at 1.6 Å revealed that the binding site was occupied by the C-terminal (C-ter) residues coming from a symmetric KPC-2 monomer, with the ultimate C-ter Glu interacting with Ser130, Lys234, Thr235, and Thr237 in the active site. This mode of binding can be paralleled to the inhibition of the TEM-1 β-lactamase by the inhibitory protein BLIP. Determination of the 1.23-Å structure of a KPC-2 mutant in which the five C-ter residues were deleted revealed that the catalytic site was filled by a citrate molecule. Structure analysis and docking simulations with cefotaxime and imipenem provided further insights into the molecular basis of the extremely broad spectrum of KPC-2, which behaves as a cefotaximase with significant activity against carbapenems. In particular, residues 104, 105, 132, and 167 draw a binding cavity capable of accommodating both the aminothiazole moiety of cefotaxime and the 6α-hydroxyethyl group of imipenem, with the binding of the former drug being also favored by a significant degree of freedom at the level of the loop at positions 96 to 105 and by an enlargement of the binding site at the end of strand β3. |
| Databáze: |
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