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Structural bases for stability-function tradeoffs in antibiotic resistance.

Veena L Thomas1, Andrea C McReynolds, Brian K Shoichet

  • 1Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California San Francisco, San Francisco, CA 94158-2518, USA.

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Enzyme evolution for antibiotic resistance often reduces protein stability. Mutations conferring new beta-lactamase activity against cephalosporins decreased stability, revealing structural mechanisms that may limit future resistance evolution.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Evolutionary Biology

Background:

  • Enzyme active site preorganization for substrate recognition can decrease protein stability.
  • The stability-activity tradeoff's impact on enzyme evolution and structural changes during new activity acquisition is not fully understood.
  • Beta-lactamases rapidly evolve antibiotic resistance, making them a model for studying these evolutionary constraints.

Purpose of the Study:

  • To investigate if protein stability constrains the evolution of antibiotic resistance in beta-lactamases.
  • To explore the structural mechanisms by which mutations confer extended-spectrum activity and affect stability.

Main Methods:

  • Investigated extended-spectrum mutants of class C beta-lactamases with evolved activity against third-generation cephalosporins.
  • Performed enzyme assays to quantify activity changes and thermodynamic stability measurements.
  • Determined X-ray crystal structures of eight mutant enzymes, including complexes with inhibitors and antibiotics.

Main Results:

  • Five mutant enzymes showed 100-200 fold increased activity against cefotaxime.
  • All mutant enzymes exhibited decreased thermodynamic stability (1.7–4.1 kcal mol(-1)).
  • X-ray crystallography revealed distinct structural mechanisms, including altered flexibility and ground-state structures, for each mutant's extended-spectrum activity.

Conclusions:

  • Mutations conferring new beta-lactamase activity against cephalosporins decrease protein stability, supporting the stability-function hypothesis.
  • The identified structural changes explain antibiotic resistance mechanisms and the associated stability loss.
  • Decreased protein stability acts as a constraint on the future evolution of antibiotic resistance.