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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
Summary
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.
