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Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis
P J Hajduk1, J Dinges, J M Schkeryantz
1Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Abstract:
The Erm family of methyltransferases confers resistance to the macrolide-lincosamide-streptogramin type B (MLS) antibiotics through the methylation of 23S ribosomal RNA. Upon the methylation of RNA, the MLS antibiotics lose their ability to bind to the ribosome and exhibit their antibiotic activity. Using an NMR-based screen, we identified a series of triazine-containing compounds that bind weakly to ErmAM. These initial lead compounds were optimized by the parallel synthesis of a large number of analogues, resulting in compounds which inhibit the Erm-mediated methylation of rRNA in the low micromolar range. NMR and X-ray structures of enzyme/inhibitor complexes reveal that the inhibitors bind to the S-adenosylmethionine binding site on the Erm protein. These compounds represent novel methyltransferase inhibitors that serve as new leads for the reversal of Erm-mediated MLS antibiotic resistance.
Insights
Researchers identified novel triazine compounds that inhibit Erm-mediated methylation of 23S ribosomal RNA, potentially reversing macrolide-lincosamide-streptogramin B antibiotic resistance by blocking enzyme activity.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Erm methyltransferases confer antibiotic resistance by methylating 23S ribosomal RNA.
- This methylation prevents macrolide-lincosamide-streptogramin B (MLS) antibiotics from binding to the ribosome.
- Reversing this resistance mechanism is crucial for effective antibiotic therapy.
Purpose of the Study:
- To identify novel inhibitors of Erm methyltransferases.
- To develop compounds that can reverse Erm-mediated MLS antibiotic resistance.
- To characterize the binding mode of these inhibitors.
Main Methods:
- NMR-based screening to identify initial lead compounds.
- Parallel synthesis and optimization of triazine analogues.
- Biochemical assays to determine inhibitory activity (low micromolar range).
- NMR and X-ray crystallography to elucidate enzyme-inhibitor complex structures.
Main Results:
- Identified triazine-containing compounds that inhibit ErmAM.
- Optimized analogues demonstrated low micromolar inhibitory activity against Erm-mediated rRNA methylation.
- Structural studies revealed inhibitors bind to the S-adenosylmethionine binding site of Erm protein.
Conclusions:
- Novel methyltransferase inhibitors targeting the S-adenosylmethionine binding site were developed.
- These compounds represent promising leads for reversing Erm-mediated MLS antibiotic resistance.
- Further development could restore the efficacy of MLS antibiotics against resistant strains.