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Antimicrobial Agents and Chemotherapy, February 2006, p. 731-738, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.731-738.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Prediction of the Evolution of Ceftazidime Resistance in Extended-Spectrum ß-Lactamase CTX-M-9

J. Delmas,1* F. Robin,1 F. Carvalho,2 C. Mongaret,1 and R. Bonnet1

Faculté de Médecine, Centre Hospitalo-Universitaire, Clermont-Ferrand, France,1 Pathogénie Bactérienne Intestinale, Université d'Auvergne, Clermont-Ferrand, France2

Received 17 August 2005/ Returned for modification 18 October 2005/ Accepted 10 November 2005

A random mutagenesis technique was used to predict the evolutionary potential of ß-lactamase CTX-M-9 toward the acquisition of improved catalytic activity against ceftazidime. Thirty CTX-M mutants were obtained during three rounds of mutagenesis. These mutants conferred 1- to 128-fold-higher MICs of ceftazidime than the parental enzyme CTX-M-9. The CTX-M mutants contained one to six amino acid substitutions. Mutants harbored the substitutions Asp240Gly and Pro167Ser, which were previously observed in clinical CTX-M enzymes. Additional substitutions, notably Arg164His, Asp179Gly, and Arg276Ser, were observed near the active site. The kinetic constants of the three most active mutants revealed two distinct ways of improving catalytic efficiency against ceftazidime. One enzyme had a 17-fold-higher kcat value than CTX-M-9 against ceftazidime. The other two had 75- to 300-fold-lower Km values than CTX-M-9 against ceftazidime. The current emergence of CTX-M ß-lactamases with improved activity against ceftazidime may therefore be the beginning of an evolutionary process which might subsequently generate a great diversity of CTX-M-type ceftazidimases.

* Corresponding author. Mailing address: Laboratoire de Bactériologie, Faculté de Médecine, 28, place H. Dunant, 63 001 Clermont-Ferrand, France. Phone: (33) 4 73 17 81 50. Fax: (33) 4 73 27 74 94. E-mail: julien.delmas{at}u-clermont1.fr.

Antimicrobial Agents and Chemotherapy, February 2006, p. 731-738, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.731-738.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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