Open AccessConvergent In Vivo and In Vitro Selection of Ceftazidime Resistance Mutations at Position 167 of CTX-M-3 β-Lactamase in Hypermutable Escherichia coli Strains
Author(s) -
M.N Stepanova,
Maxim Pimkin,
A. Nikulin,
Varvara K. Kozyreva,
Е. Д. Агапова,
Mikhail V. Edelstein
Publication year - 2008
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01060-07
Subject(s) - ceftazidime , cefotaxime , escherichia coli , microbiology and biotechnology , biology , ampicillin , enterobacteriaceae , typing , cephalosporin , antibiotics , gene , genetics , bacteria , pseudomonas aeruginosa
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 hypermutableEscherichia coli nosocomial isolate (isolate Irk2320) and is a Pro167Thr amino acid substitution variant of CTX-M-3. By molecular typing of ESBL-producingE. 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 inbla CTX-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.