TrmD: A Promising Antibacterial Target and Its Small-Molecule Inhibitors

Bacterial tRNA-(N1G37) methyltransferase (TrmD), a member of the SPOUT superfamily, plays a pivotal role in catalyzing the methyl group transfer from S-adenosyl-l-methionine to the N1 position of G37 in the pathway of post-transcriptional modifications of bacterial tRNA. In response to the urgent global clinical need to overcome antibiotic resistance, inhibiting TrmD activity has emerged as a novel strategy for combating various antimicrobial-resistant bacterial strains. Various rational drug discovery strategies, including fragment-based drug design, high-throughput screening, click chemistry-based direct-to-biology screening, virtual screening, molecular hybridization, and prodrug strategy, have been successfully employed to identify small-molecule TrmD inhibitors with diverse scaffolds. Here, we highlight discovery strategies, molecular structural features, and key structure-activity relationships that have driven the discovery and development of small-molecule TrmD inhibitors; discuss the key factors underlying the gap between enzymatic inhibitory potency and in vitro antibacterial activity of small-molecule TrmD inhibitors; and offer insights for bridging it.