Inhibition of Helicobacter pylori Glu‐tRNAGln amidotransferase by novel analogues of the putative transamidation intermediate

Glutaminyl-tRNA(Gln) in Helicobacter pylori is formed by an indirect route requiring a noncanonical glutamyl-tRNA synthetase and a tRNA-dependent heterotrimeric amidotransferase (AdT) GatCAB. Widespread use of this pathway among prominent human pathogens, and its absence in the mammalian cytoplasm, identify AdT as a target for the development of antimicrobial agents. We present here the inhibitory properties of three dipeptide-like sulfone-containing compounds analogous to the transamidation intermediates, which are competitive inhibitors of AdT with respect to Glu-tRNA(Gln). Molecular docking revealed that AdT inhibition by these compounds depends on - stacking interactions between their aromatic groups and Tyr81 of the GatB subunit. The properties of these inhibitors indicate that the 3-terminal adenine of Glu-tRNA(Gln) plays a major role in binding to the AdT transamidation active site.