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

Abstract

Glutaminyl-tRNAGln 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-tRNAGln. Molecular docking revealed that AdT inhibition by these compounds depends on π–π 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-tRNAGln plays a major role in binding to the AdT transamidation active site.