Nanoscale direct-to-biology optimization and structural insights into selective S. aureus TrmD inhibitors

DOI: 10.1021/acs.jmedchem.5c02323

Authors: Ariane F. Hübner (Johannes Gutenberg-University) , Annabelle C. Weldert (Johannes Gutenberg-University) , Tessa Marciniak (University of Würzburg) , Florian Hof (Johannes Gutenberg-University) , Vivien S. Beck (University of Würzburg) , Samuel Carien (University of Würzburg) , Sophie N. Mulartschyk (Johannes Gutenberg-University) , Eva Wolf (Johannes Gutenberg-University) , Wilma Ziebuhr (University of Würzburg) , Fabian Barthels (Johannes Gutenberg-University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2025
Diamond Proposal Number(s): 36097

Abstract: The tRNA m1G37 methyltransferase (TrmD) is considered essential in various bacteria, including Staphylococcus aureus, a pathogen responsible for a wide range of diseases. Here, we have performed a high-throughput nanomole-scale synthesis campaign (nanoSAR) by late-stage copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC)-functionalizing a library of structurally diverse azides (N = 320) to a pyrrolopyrimidone alkyne. We have identified selective S. aureus TrmD inhibitors with inhibitory activity in the nanomolar to low micromolar range using a direct-to-biology assay read-out. A carbamate-masked guanidine intermediate of the lead structure selectively inhibited S. aureus growth at low micromolar concentrations in cell-based assays, while Gram-negative bacteria and an off-target panel of methyltransferases were not affected. Subsequent cocrystallization resulted in a crystal structure of S. aureus TrmD bound to an inhibitor, providing detailed insights into its binding mode and enabling future structure-guided optimization.

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Medicine, Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Added On: 10/12/2025 13:39

Documents:
nanoscale-direct-to-biology-optimization-and-structural-insights-into-selective-s-aureus-trmd-inhibitors.pdf

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)