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Design, Synthesis, and Evaluation of Novel Inhibitors of Aminoglycoside-Resistance 16S Ribosomal RNA
Benjamin E Deprez1, Debayan Dey2, Natalia Zelinskaya2
1Department of Chemistry, Emory University, Atlanta, Georgia, 30322, USA.
Abstract:
One of the major mechanisms of resistance to ribosome-targeting antibiotics is the modification of ribosomal RNA (rRNA). Specific methyltransferase enzymes, for example, confer high-level resistance to aminoglycosides by selectively methylating the 16S rRNA in the ribosomal decoding center. These enzymes have been detected globally and pose a threat to the continued use of aminoglycosides. Compound 1, a dehydroamino amide inhibitor of the m1A1408 methyltransferase NpmA, was previously disclosed and identified using high-throughput virtual screening. Here, the synthesis and biological evaluation of rationally designed analogs of 1 has been reported. Guided by molecular docking, additional putative inhibitors of NpmA, as well as the functionally related m7G1405 methyltransferase RmtB, varying in each region of the original scaffold are disclosed. A modular, fragment-based synthesis enables access to 17 analogs, which exhibits mixed activity against NpmA and RmtB, including several that are selective for RmtB. The structure-activity relationship determined for the dehydroamino amide series will guide continued research against this target class with the aim of developing a toolkit for selective- or pan-16S rRNA methyltransferase inhibition.
Insights
Researchers synthesized and tested analogs of a compound that inhibits NpmA, a methyltransferase enzyme. This work aims to develop new tools to combat antibiotic resistance by targeting 16S ribosomal RNA methyltransferases.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Antimicrobial Resistance
Background:
- Ribosomal RNA (rRNA) modification is a key mechanism of antibiotic resistance.
- Methyltransferase enzymes that modify 16S rRNA confer high-level resistance to aminoglycosides.
- These enzymes are globally prevalent, threatening the efficacy of existing antibiotics.
Purpose of the Study:
- To synthesize and biologically evaluate rationally designed analogs of a dehydroamino amide inhibitor (Compound 1).
- To identify novel inhibitors targeting the methyltransferase enzymes NpmA (m1A1408) and RmtB (m7G1405).
- To guide future research towards developing selective or pan-16S rRNA methyltransferase inhibitors.
Main Methods:
- Rational drug design guided by molecular docking.
- Synthesis of 17 dehydroamino amide analogs using a modular, fragment-based approach.
- Biological evaluation of synthesized analogs against NpmA and RmtB methyltransferases.
Main Results:
- Successful synthesis of 17 analogs of Compound 1.
- Demonstrated mixed inhibitory activity against NpmA and RmtB.
- Identified several analogs with selectivity for the RmtB methyltransferase.
Conclusions:
- The structure-activity relationship of the dehydroamino amide series was determined.
- This research provides a foundation for developing novel inhibitors of 16S rRNA methyltransferases.
- The findings contribute to efforts to overcome aminoglycoside resistance.
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