Trans-translation machinery

The trans-translation machinery in Mycobacterium tuberculosis is a specialized ribosome rescue system consisting of transfer-messenger RNA (tmRNA) and Small protein B (SmpB) (Keiler, 2015, Nature Reviews Microbiology). This pathway is crucial for the survival of M. tuberculosis within the hostile, acidic, and energy-stressed environment of host macrophages, where it prevents the accumulation of stalled ribosomes on damaged or truncated mRNAs (Shi et al., 2011, Science; Personne & Parish, 2014, Journal of Bacteriology). By facilitating the release of these ribosomes and tagging the resulting incomplete proteins for proteolysis, the system ensures the recycling of translational components and maintains cellular proteostasis. The importance of this pathway is highlighted by the mechanism of the first-line drug pyrazinamide, which, in its active form pyrazinoic acid, binds to ribosomal protein S1 (RpsA) to inhibit trans-translation (Shi et al., 2011). Because this rescue mechanism is unique to bacteria and absent in humans, it serves as an attractive target for novel antibiotic development. Recent research has identified several experimental compounds, such as MBX-4132 and KKL-1005, that specifically inhibit this process to kill both actively growing and persistent mycobacteria (Varshney et al., 2025, ACS Infectious Diseases; Alumasa et al., 2017, Antimicrobial Agents and Chemotherapy).

Other names

tmRNA-SmpB systemRibosome rescue pathwaySsrA-SmpB complexRibosomal protein S1 (RpsA)30S ribosomal protein S1Ribosomal protein bL12

Inhibition of the trans-translation ribosome rescue pathway by binding to essential components such as ribosomal protein S1 (RpsA) or bL12, which prevents the rescue of stalled ribosomes and leads to the accumulation of toxic truncated proteins and depletion of the active ribosome pool.