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bioRxiv · 10.1101/2025.06.02.656638

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

Varshney, A.·Alumasa, J. N.·Miller, A. R.·Keiler, K. C.
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Abstract

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.

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Varshney, A., Alumasa, J. N., Miller, A. R., Keiler, K. C.. 2025-06-02. A trans-translation inhibitor kills Mycobacterium tuberculosis by targeting ribosomal protein bL12. https://doi.org/10.1101/2025.06.02.656638

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