Convergent in vivo and in vitro selection of ceftazidime resistance mutations at position 167 of CTX-M-3 beta-lactamase in hypermutable Escherichia coli strains.

Antimicrobial Agents and Chemotherapy
Marina N StepanovaMikhail V Edelstein

Abstract

We report on a novel CTX-M extended-spectrum beta-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 beta-lactamase. To reproduce the natural evolution of CTX-M-3, we selected for ceftazidime resistance mutations in bla CTX-M-3 gene in vitro both in clinical isolate Irk1224 and in laboratory-derived hypermutable (mutD5) strain GM2995. These experiments yielded CTX-M-3 Pro167Ser and CTX-M-3 Asn136Lys mutants which conferred higher levels of resistance to ceftazidime than to cefotaxime. CTX-M-3 Asn136Lys 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.

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Citations

Apr 30, 2008·Antimicrobial Agents and Chemotherapy·Angela NovaisJuan Carlos Galán
Mar 25, 2009·Antimicrobial Agents and Chemotherapy·Alessandra Carattoli
May 23, 2014·The Journal of Antimicrobial Chemotherapy·Astrid PérezGermán Bou
Feb 9, 2010·International Journal of Antimicrobial Agents·Guo-Bao TianYohei Doi
Jun 16, 2012·Critical Reviews in Microbiology·Wei-Hua Zhao, Zhi-Qing Hu
May 23, 2014·Drug Discovery Today. Technologies·Anne Jolivet-Gougeon, Martine Bonnaure-Mallet
Apr 11, 2012·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·O V ShevchenkoM V Edelstein
Dec 24, 2008·Animal Health Research Reviews·Patrick Boerlin, Richard J Reid-Smith

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