A-translation inhibitor that targets ribosomal protein bL12 kills.

New antibiotics with novel mechanisms of action are needed to treat infections by multidrug-resistant strains of. Here, we show that KKL-1005, an anti-tubercular triazole-based molecule, binds to ribosomal protein bL12 and specifically inhibits the-translation ribosome rescue pathway, a process essential for the survival of. Our data demonstrate that KKL-1005 binds to the N-terminal domain of bL12, bothand in bacterial cells, and specifically inhibits-translation and not normal translation. These results suggest that tmRNA-SmpB interacts with bL12 differently from tRNA and raise the possibility of developing antibiotics targeting bL12.IMPORTANCETuberculosis continues to be a leading cause of death worldwide, and antibiotics that target new pathways are urgently needed.-Translation is a ribosome rescue pathway required for the survival of. We identified a small molecule, KKL-1005, that specifically inhibits-translation without affecting translation from a library of compounds that prevent the growth of. KKL-1005 targets bacterial ribosomal protein bL12, which is essential for the recruitment and activation of GTPase translation factors. The specificity of KKL-1005 for-translation indicates that bL12 interacts differently with the translation machinery during-translation than during canonical translation. KKL-1005 is bactericidal against, suggesting that inhibiting-translation by targeting bL12 is a new strategy for developing antibiotics against drug-resistant infections.