Article (Scientific journals)
Kinetic and crystallographic studies of extended-spectrum GES-11, GES-12, and GES-14 β-lactamases.
Delbrück, Heinrich; Bogaerts, Pierre; Kupper, Michaël et al.
2012In Antimicrobial Agents and Chemotherapy, 56(11), p. 5618-5625
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Abstract :
[en] GES-1 is a class A extended-spectrum β-lactamase conferring resistance to penicillins, narrow- and expanded-spectrum cephalosporins, and ceftazidime. However, GES-1 poorly hydrolyzes aztreonam and cephamycins and exhibits very low k(cat) values for carbapenems. Twenty-two GES variants have been discovered thus far, differing from each other by 1 to 3 amino acid substitutions that affect substrate specificity. GES-11 possesses a Gly243Ala substitution which seems to confer to this variant an increased activity against aztreonam and ceftazidime. GES-12 differs from GES-11 by a single Thr237Ala substitution, while GES-14 differs from GES-11 by the Gly170Ser mutation, which is known to confer increased carbapenemase activity. GES-11 and GES-12 were kinetically characterized and compared to GES-1 and GES-14. Purified GES-11 and GES-12 showed strong activities against most tested β-lactams, with the exception of temocillin, cefoxitin, and carbapenems. Both variants showed a significantly increased rate of hydrolysis of cefotaxime, ceftazidime, and aztreonam. On the other hand, GES-11 and GES-12 (and GES-14) variants all containing Ala243 exhibited increased susceptibility to classical inhibitors. The crystallographic structures of the GES-11 and GES-14 β-lactamases were solved. The overall structures of GES-11 and GES-14 are similar to that of GES-1. The Gly243Ala substitution caused only subtle local rearrangements, notably in the typical carbapenemase disulfide bond. The active sites of GES-14 and GES-11 are very similar, with the Gly170Ser substitution leading only to the formation of additional hydrogen bonds of the Ser residue with hydrolytic water and the Glu166 residue.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Delbrück, Heinrich;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH
Bogaerts, Pierre;  Université Catholique de Louvain - UCL > CHU Mont-Godinne
Kupper, Michaël;  RWTH
Rezende de Castro, Roberta;  Université Catholique de Louvain - UCL > CHU Mont-Godinne
Bennik, Sandra;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH
Glupczynski, Youri;  Université Catholique de Louvain - UCL > CHU Mont-Godinne
Galleni, Moreno ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Hoffmann, Kurt;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH
Bebrone, Carine ;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH
Language :
English
Title :
Kinetic and crystallographic studies of extended-spectrum GES-11, GES-12, and GES-14 β-lactamases.
Publication date :
November 2012
Journal title :
Antimicrobial Agents and Chemotherapy
ISSN :
0066-4804
eISSN :
1098-6596
Publisher :
American Society for Microbiology (ASM), Washington, United States - District of Columbia
Volume :
56(11)
Pages :
5618-5625
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
AvH - Alexander von Humboldt-Stiftung
Available on ORBi :
since 22 February 2013

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