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The Use of a &#946;-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions
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Substitutions at position 105 in SHV family β-lactamases decrease catalytic efficiency and cause inhibitor

Mei Li1, Benjamin C Conklin, Magdalena A Taracila

  • 1Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Antimicrobial Agents and Chemotherapy
|August 22, 2012
PubMed
Summary
This summary is machine-generated.

Mutations at position 105 in beta-lactamases can confer resistance to clavulanic acid. This study explored SHV-1 variants, finding some mutations increase resistance and reduce enzyme efficiency, impacting inhibitor design.

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Area of Science:

  • Biochemistry
  • Microbiology
  • Drug Discovery

Background:

  • Ambler class A beta-lactamases are key targets for antibiotic development.
  • Clavulanic acid is a crucial beta-lactamase inhibitor, but resistance mechanisms are emerging.
  • Position 105 in beta-lactamases is hypothesized to play a role in inhibitor resistance.

Purpose of the Study:

  • To investigate the impact of substitutions at position 105 of SHV-1 beta-lactamase on resistance to clavulanic acid and penem inhibitors.
  • To understand the biochemical basis of resistance conferred by mutations at position 105.
  • To assess the potential for resistance to novel bicyclic 6-methylidene penems.

Main Methods:

  • Site-directed mutagenesis was used to create 19 variants of SHV-1 at position 105.
  • Antimicrobial susceptibility testing (MIC) was performed on Escherichia coli expressing these variants.
  • Enzyme kinetics (K(m), K(i)) were determined for wild-type and mutant enzymes with various substrates and inhibitors.
  • Molecular modeling was employed to analyze the structural basis of resistance.

Main Results:

  • Several Y105 variants of SHV-1 exhibited elevated minimum inhibitory concentrations (MICs) to ampicillin-clavulanate.
  • Mutations at position 105 led to reduced catalytic efficiency against ampicillin and nitrocefin for some variants.
  • While affinity for penem inhibitors decreased, susceptibility was generally retained.
  • Modeling suggested resistance arises from oxyanion hole distortion.

Conclusions:

  • Residue 105 is critical for SHV-1 function and is a key site for developing resistance to clavulanic acid.
  • Mutations at this position can lead to resistance phenotypes similar to those observed in carbapenemase KPC-2.
  • Understanding the role of residue 105 is vital for designing next-generation beta-lactamase inhibitors.