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Updated: Jul 17, 2026
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Isolation and Identification of Waterborne Antibiotic-Resistant Bacteria and Molecular Characterization of their Antibiotic Resistance Genes
Published on: March 3, 2023
Hydration and hydrolysis define antibiotic resistance conferred by macrolide esterases
Emma T R Kelly1,2,3, Iryna Myziuk4, Mark Z Hemmings1,2,3
1Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
Summary
Bacteria are developing resistance to macrolide antibiotics through enzymes called macrolide esterases. This study reveals how Est-type esterases bind to macrolides, offering insights for developing new antibiotics.
Area of Science:
- Microbiology
- Biochemistry
- Structural Biology
Background:
- Macrolide antibiotics are crucial in human and veterinary medicine but face widespread bacterial resistance.
- Enzyme-mediated inactivation, particularly by macrolide esterases, is a significant mechanism of macrolide resistance.
- Est-type macrolide esterases, belonging to the α/β-hydrolase superfamily, represent a recently identified class of resistance enzymes.
Purpose of the Study:
- To conduct detailed structure-function studies on four diverse Est-type macrolide esterases.
- To elucidate the structural basis of macrolide-enzyme interactions and substrate specificity.
- To provide insights for the development of next-generation antibiotics.
Main Methods:
- X-ray crystallography to determine enzyme structures, including complexes with macrolides.
- Resistance profiling and substrate specificity assays.
- Mutational and kinetic studies to analyze enzyme-macrolide interactions.
Main Results:
- Detailed structures of four Est-type esterases (EstTSf, EstTSt, EstTBc, EstXEc) were determined.
- Structures of EstTBc and EstXEc in complex with tylosin and tylvalosin, post-hydrolysis, were elucidated.
- Analysis revealed that promiscuous binding and imprecise positioning, facilitated by a water-cage, govern substrate specificity.
Conclusions:
- Est-type macrolide esterases exhibit substrate specificity influenced by flexible binding mechanisms.
- Understanding these interactions is key to overcoming macrolide resistance.
- The findings offer a foundation for designing novel antibiotics that circumvent existing resistance strategies.
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