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


Randegger, C C; Hachler, H (2001). Amino acid substitutions causing inhibitor resistance in TEM -lactamases compromise the extended-spectrum phenotype in SHV extended-spectrum -lactamases. Journal of Antimicrobial Chemotherapy, 47(5):547-554.

Abstract

Three amino acid substitutions, Met-69→Ile, Arg-244→Ser and/or Asn-276→Asp, mediate inhibitor resistance (IR) in TEM β-lactamases. They were introduced in all possible combinations at homologous positions into either SHV-1 or the respective extended-spectrum β-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 β-lactam formulations. This decrease over-compensated for the expected increase in inhibitor resistance, so that most mutants showed no rise in resistance to inhibitor/β-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 β-lactamase does not benefit proportionally from simultaneous substitution of residues relevant for the ESBL and the IR phenotype

Abstract

Three amino acid substitutions, Met-69→Ile, Arg-244→Ser and/or Asn-276→Asp, mediate inhibitor resistance (IR) in TEM β-lactamases. They were introduced in all possible combinations at homologous positions into either SHV-1 or the respective extended-spectrum β-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 β-lactam formulations. This decrease over-compensated for the expected increase in inhibitor resistance, so that most mutants showed no rise in resistance to inhibitor/β-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 β-lactamase does not benefit proportionally from simultaneous substitution of residues relevant for the ESBL and the IR phenotype

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Pharmacology
Health Sciences > Microbiology (medical)
Health Sciences > Infectious Diseases
Health Sciences > Pharmacology (medical)
Language:English
Date:1 May 2001
Deposited On:25 Sep 2018 14:29
Last Modified:07 Aug 2020 21:53
Publisher:Oxford University Press
ISSN:0305-7453
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/jac/47.5.547
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101093jac475547 (Library Catalogue)

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