Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis

Tuberculosis (TB) is a disease cause by Mycobacterium tuberculosis, a bacterium that usually attacks the lungs. People can contract an infection through inhalation of the bacteria; however, not everyone infected by the bacteria will become sick. In some cases, the body’s defense system attacks the bacteria and suppresses its activity. This is known as a latent infection. Individuals with this type of infection do not show signs or symptoms of tuberculosis, nor can they pass the bacteria on to others. If the body cannot fight the infection, the bacteria will replicated quickly causing the TB disease. According to the Centers for Disease Control, TB was once the leading cause of death in the United States.

TB can be treated by taking a variety of medications over the course of six to twelve months. For optimal effectiveness, tuberculosis drugs such as isoniazid and rifampin should be used in conjunction with pyrazinamide (PZA). The molecular mechanism of PZA was unknown until recently.

Scientists initially hypothesized that PZA worked by inhibiting fatty acid synthesis by acting on Fatty Acid Synthase I (FASI). They also theorized that PZA disrupted the bacterial membrane potential via the diffusion of pyrazinoic acid (POA), the active form of PZA. However, neither of these hypotheses yielded a satisfactory mechanism for the action of PZA.

Earlier this year, Shi and his team investigated the molecular mechanism of PZA. Affinity chromatography showed that the bacteria’s RpsA protein was the most likely target for POA. Additionally, they found that at high concentrations of POA, the transfer messenger RNA (tmRNA) was inhibited from binding to RpsA. Transfer messenger RNA plays a critical role in trans-translation, a process that “rescues” and resets stalled ribosomes. The tmRNA displaces the stalled mRNA from the ribosome, tags the nascent peptide for degradation, and marks the abnormal mRNA for degradation. In other words, by binding RspA, POA fatally inhibits the process of trans-translation which limits M. tuberculosis cell survivability.

These results are very significant. Not only do they show the molecular mechanism of an important tuberculosis drug, but they revealed trans-translation as a possible target mechanism which can be used in the design of future antibiotics.

Shi, Wanliang, et al., “Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis” Science 333 (2011): 1630-1632. ww.sciencemag.org. American Association for the Advancement of Science, 16 September 2011. Web. 1 December 2011.