Abstract
Tuberculosis (TB) is recognized as the second leading cause of death globally from a single infectious agent, following SARS-CoV-2 pneumonia. Aminoacyl-tRNA synthetases (aaRS) are essential enzymes responsible for attaching amino acids to their cognate tRNAs. These enzymes represent a promising set of targets for selective drug design due to the divergence between prokaryotic and eukaryotic aaRS. Recently, a new class of 3-aminopyrazine- 2-carboxamide derivatives has been identified as potent inhibitors of prolyl-tRNA synthetase (ProRS) from Mycobacterium tuberculosis (Mtb). These compounds exhibit significant antimycobacterial activity against Multi Drug Resistant strains of Mtb and demonstrate cytotoxicity against HepG2 human hepatocellular carcinoma cells. In this study, we present the crystal structures of MtbProRS in complex with five distinct 3-aminopyrazine-2-carboxamide derivatives. Structural analysis reveals that these inhibitors compete with ATP for the binding site of MtbProRS. Importantly, a critical hydrogen bond between the Glu144 of MtbProRS and the amino group of the carboxamide is identified, providing insights into the selective inhibition of MtbProRS over human ProRS.