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Journal of Antimicrobial Chemotherapy (2001) 47, 547-554
© 2001 The British Society for Antimicrobial Chemotherapy

Amino acid substitutions causing inhibitor resistance in TEM ß-lactamases compromise the extended-spectrum phenotype in SHV extended-spectrum ß-lactamases

Corinne C. Randegger and Herbert Hächler,*

Institute of Medical Microbiology, University of Zürich, PO Box, CH-8028 Zürich, Switzerland

Three amino acid substitutions, Met-69->Ile, Arg-244->Ser and/or Asn-276->Asp, mediate inhibitor resistance (IR) in TEM ß-lactamases. They were introduced in all possible combinations at homologous positions into either SHV-1 or the respective extended-spectrum ß-lactamases (ESBLs), SHV-2 or SHV-5. Susceptibility testing of the resulting set of seven variants of each parental strain, all in an isogenic background, was performed. The phenotypes of the constructions revealed that most substitutions resulted in reduced resistance to most tested single ß-lactam formulations. This decrease over-compensated for the expected increase in inhibitor resistance, so that most mutants showed no rise in resistance to inhibitor/ß-lactam combinations, although increases of MICs from one- to 43-fold compared with the respective parental strains were also measured. Combination of several IR-determining substitutions impaired both phenotypes in the carrier strains even more. None of the 14 mutants derived from the ESBLs, SHV-2 and SHV-5, showed a clinically relevant combined ESBL–IR phenotype. These findings indicate that the SHV ß-lactamase does not benefit proportionally from simultaneous substitution of residues relevant for the ESBL and the IR phenotype.

* Corresponding author. Tel: +41-1-634-26-48; Fax: +41-1-634-49-06; E-mail: haechler{at}immv.unizh.ch


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