tRNA Methylation as an Antibacterial Target (360G-Wellcome-202192_Z_16_Z)

In response to the continued evolution of bacterial resistance to antibiotics, the discovery and exploitation of novel bacterial target mechanisms, such as essential enzymes, is increasingly important to feed novel candidates into the antibiotic discovery pipeline. tRNA m(1)G37 methyltransferase (TrmD), catalyses the post-transcriptional methylation of guanine 37 in specific bacterial tRNAs, which is an essential step. Deletion mutants for this enzyme in both gram negative and gram positive bacteria causes an increase in translational errors, decelerated growth and cell death. Substantial structural differences have been identified between TrmD and the human equivalent (Trm5), strongly suggesting the development of highly selective inhibitors for TrmD should be possible, thus reducing the probability of off-target toxicity. Current TrmD inhibitors show promising in vitro potency (micromolar range), but their low activity against cultured bacteria is proposed to arise from poor bacterial uptake of the compounds (inefficient crossing of the bacterial cell wall). Our objective is to design, prepare and biologically evaluate a small library of novel TrmD inhibitors. These compounds will feature a range of modifications selected to enhance bacterial cell uptake. The activity of these compounds will be measured by comparing in vitro potency with activity in bacterial cultures.