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Antimicrobial Agents and Chemotherapy, April 2008, p. 1297-1301, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01060-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Convergent In Vivo and In Vitro Selection of Ceftazidime Resistance Mutations at Position 167 of CTX-M-3 β-Lactamase in Hypermutable Escherichia coli Strains{triangledown}

Marina N. Stepanova,1 Maxim Pimkin,1,{dagger} Anatoly A. Nikulin,1 Varvara K. Kozyreva,1 Elena D. Agapova,2 and Mikhail V. Edelstein1*

Institute of Antimicrobial Chemotherapy, Smolensk, Russia,1 Regional Children's Hospital, Irkutsk, Russia2

Received 11 August 2007/ Returned for modification 23 September 2007/ Accepted 31 December 2007

We report on a novel CTX-M extended-spectrum β-lactamase (ESBL), designated CTX-M-42, with enhanced activity toward ceftazidime. CTX-M-42 was identified in a hypermutable Escherichia coli nosocomial isolate (isolate Irk2320) and is a Pro167Thr amino acid substitution variant of CTX-M-3. By molecular typing of ESBL-producing E. coli strains previously isolated in the same hospital ward, we were able to identify a putative progenitor (strain Irk1224) of Irk2320, which had a mutator phenotype and harbored the CTX-M-3 β-lactamase. To reproduce the natural evolution of CTX-M-3, we selected for ceftazidime resistance mutations in blaCTX-M-3 gene in vitro both in clinical isolate Irk1224 and in laboratory-derived hypermutable (mutD5) strain GM2995. These experiments yielded CTX-M-3Pro167Ser and CTX-M-3Asn136Lys mutants which conferred higher levels of resistance to ceftazidime than to cefotaxime. CTX-M-3Asn136Lys had a level of low activity toward ampicillin, which may explain its absence from clinical isolates. We conclude that the selection of CTX-M-42 could have occurred in vivo following treatment with ceftazidime and was likely facilitated by the hypermutable background.

* Corresponding author. Mailing address: Institute of Antimicrobial Chemotherapy, Krupskaya str. 28, P.O. Box 5, Smolensk, Russia. Phone: 7-4812-450602. Fax: 7-4812-450602-123. E-mail: me{at}antibiotic.ru

{triangledown} Published ahead of print on 22 January 2008.

{dagger} Present address: Fox Chase Cancer Center, Philadelphia, PA.

Antimicrobial Agents and Chemotherapy, April 2008, p. 1297-1301, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01060-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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