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In vitro tRNA Methylation Assay with the Entamoeba histolytica DNA and tRNA Methyltransferase Dnmt2 (Ehmeth) Enzyme
Published on: October 19, 2010
EmtA, a rRNA methyltransferase conferring high-level evernimicin resistance
P A Mann1, L Xiong, A S Mankin
1Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Molecular Microbiology
|October 3, 2001
Summary
A novel mechanism of evernimicin resistance in Enterococcus faecium involves the emtA gene, encoding a methyltransferase that modifies 23S rRNA. This modification, at residue G2470, directly blocks evernimicin binding to ribosomes, explaining drug resistance.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Resistance
Background:
- Enterococcus faecium strain 9631355 displays resistance to avilamycin and evernimicin.
- Evernimicin is a potential human therapeutic agent.
- Ribosomes from resistant strains show reduced evernimicin binding.
Purpose of the Study:
- To elucidate the molecular mechanism of evernimicin resistance in Enterococcus faecium.
- To identify and characterize the genetic determinant responsible for evernimicin resistance.
Main Methods:
- Isolation and characterization of resistant Enterococcus faecium strain.
- Cloning and sequencing of the resistance determinant (emtA).
- In vitro assays including cell-free translation, direct-binding assays, and RNA footprinting.
Main Results:
- Identified and cloned the emtA gene, encoding an evernimicin methyltransferase.
- Demonstrated that emtA is plasmid-borne and confers transmissible resistance.
- EmtA methylates 50S ribosomal subunits at residue G2470 in 23S rRNA.
- Methylation at G2470 directly interferes with evernimicin binding to the ribosome.
Conclusions:
- The emtA gene and its methyltransferase activity are responsible for evernimicin resistance in E. faecium.
- This resistance mechanism involves direct modification of the drug-binding site on the ribosome.
- Understanding this mechanism is crucial for the development of effective evernimicin-based therapies.
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