Document Type

Article

Publication Date

6-10-2026

Comments

This article is the author's final published version in ACS Medicinal Chemistry Letters, Volume 17, Issue 8, 2026, Pages 1766–1779.

The published version is available at https://doi.org/10.1021/acsmedchemlett.6c00164. Copyright © 2026 American Chemical Society.

Abstract

Bacterial tRNA (m1G37) methyltransferase (TrmD) is an essential enzyme required for accurate translation and represents an attractive antibacterial target distinct from its eukaryotic counterpart, Trm5. Here, we describe the development of nicotinamide-based TrmD inhibitors incorporating electrophilic Michael-acceptor motifs to enhance cellular antibacterial activity. Mass spectrometry-based peptide mapping shows covalent modification of TrmD at Cys112, a residue proximal to the AdoMet (S-adenosylmethionine) binding region, providing a mechanistic basis for covalent target engagement. Consistent with this mechanism, electrophile-containing analogues showed improved antibacterial activity compared with the parent scaffold. In bacterial growth inhibition assays, selected compounds displayed greater functional specificity for TrmD-driven growth suppression relative to human Trm5, supporting preferential bacterial target engagement. Collectively, these results establish Cys112 as a chemically addressable site for covalent inhibition of TrmD and provide a foundation for the development of TrmD-directed antibacterial agents.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.