A trans-translation inhibitor kills Mycobacterium tuberculosis by targeting ribosomal protein bL12

New antibiotics with novel mechanisms of action are needed to treat infections by multidrug-resistant strains of Mycobacterium tuberculosis. Here, we show that KKL-1005, an anti-tubercular triazole-based molecule, binds to ribosomal protein bL12 and specifically inhibits the trans-translation ribosome rescue pathway, a process essential for the survival of M. tuberculosis. Our data demonstrate that KKL-1005 binds to the N terminal domain of bL12, both in vitro and in bacterial cells, and specifically inhibits trans-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.