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Expanded Substrate Activity of OXA-24/40 in Carbapenem-Resistant Acinetobacter baumannii Involves Enhanced Binding

Michael W Staude1, David A Leonard2, Jeffrey W Peng1

  • 1Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.

Biochemistry
|October 27, 2016
PubMed

Insights

A mutation in OXA-24/40 beta-lactamase enhances its activity against advanced antibiotics. This study reveals how protein dynamics changes contribute to antibiotic resistance in Gram-negative bacteria.

Area of Science:

  • Microbiology
  • Biochemistry
  • Structural Biology

Background:

  • Gram-negative bacteria employ beta-lactamase enzymes to resist beta-lactam antibiotics.
  • Clinical isolates exhibit beta-lactamase variants with mutations conferring "gain-of-activity," broadening antibiotic inactivation.
  • Understanding these mutations is crucial for combating rising antibiotic resistance.

Purpose of the Study:

  • To investigate the impact of a specific mutation (P227S) on the activity of OXA-24/40, a carbapenem-hydrolyzing class D beta-lactamase (CHDL).
  • To elucidate the role of protein conformational dynamics in the expanded substrate activity of beta-lactamases.

Main Methods:

  • Utilized solution-state Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Compared site-specific backbone dynamics between wild-type OXA-24/40 and its P227S variant.
  • Analyzed Acinetobacter baumannii clinical isolates.

Main Results:

  • The P227S mutation in OXA-24/40 expanded its activity to include advanced cephalosporins and aztreonam.
  • This mutation altered local backbone flexibility in key regions involved in substrate binding and hydrolysis.
  • Demonstrated a link between mutation-induced dynamics and broadened substrate specificity.

Conclusions:

  • Mutation-induced changes in protein dynamics can enhance beta-lactamase activity against a wider range of antibiotics.
  • Protein conformational dynamics play a significant role in the evolution of antibiotic resistance.
  • This is the first NMR study detailing CHDL conformational dynamics and its role in expanding beta-lactam resistance.

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