Literature

Abstract

The post-transcriptional modifier tRNA-(N1G37) methyltransferase (TrmD) has been proposed to be essential for growth in many Gram-negative and Gram-positive pathogens, however previously reported inhibitors show only weak antibacterial activity. In this work, optimisation of fragment hits resulted in compounds with low nanomolar TrmD inhibition incorporating features designed to enhance bacterial permeability and covering a range of physicochemical space. The resulting lack of significant antibacterial activity suggests that whilst TrmD is highly ligandable, its essentiality and druggability are called into question.

DOI： 10.1016/j.bmcl.2023.129331

Evaluating the druggability of TrmD, a potential antibacterial target, through design and microbiological profiling of a series of potent TrmD inhibitors

Bioorganic & Medicinal Chemistry Letters 2023.0

Selective Inhibitors of Bacterial t-RNA-(N1G37) Methyltransferase (TrmD) That Demonstrate Novel Ordering of the Lid Domain

Journal of Medicinal Chemistry 2013.0

Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism

Journal of Medicinal Chemistry 2019.0

Structure–activity relationships of novel antibacterial translation inhibitors: 3,5-Diamino-piperidinyl triazines

Bioorganic & Medicinal Chemistry Letters 2006.0

Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent gram-Positive antibacterial activity

Bioorganic & Medicinal Chemistry Letters 2003.0

Novel Inhibitors of Erm Methyltransferases from NMR and Parallel Synthesis