Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis

Wanliang Shi, Xuelian Zhang, Xin Jiang, Haiming Yuan, Jong Seok Lee, Clifton E. Barry, Honghai Wang, Wenhong Zhang, Ying Zhang

Research output: Contribution to journalArticle

Abstract

Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase, encoded by pncA), an enzyme frequently lost in PZA-resistant strains, but the target of POA in Mycobacterium tuberculosis has remained elusive. Here, we identify a previously unknown target of POA as the ribosomal protein S1 (RpsA), a vital protein involved in protein translation and the ribosome-sparing process of trans-translation. Three PZA-resistant clinical isolates without pncA mutation harbored RpsA mutations. RpsA overexpression conferred increased PZA resistance, and we confirmed that POA bound to RpsA (but not a clinically identified ΔAla mutant) and subsequently inhibited trans-translation rather than canonical translation. Trans-translation is essential for freeing scarce ribosomes in nonreplicating organisms, and its inhibition may explain the ability of PZA to eradicate persisting organisms.

Original languageEnglish (US)
Pages (from-to)1630-1632
Number of pages3
JournalScience
Volume333
Issue number6049
DOIs
StatePublished - Sep 16 2011

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Pyrazinamide
Mycobacterium tuberculosis
Ribosomes
Tuberculosis
Mutation
Protein Biosynthesis
Drug Therapy
pyrazinoic acid
Enzymes
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • General

Cite this

Shi, W., Zhang, X., Jiang, X., Yuan, H., Lee, J. S., Barry, C. E., ... Zhang, Y. (2011). Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science, 333(6049), 1630-1632. https://doi.org/10.1126/science.1208813

Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. / Shi, Wanliang; Zhang, Xuelian; Jiang, Xin; Yuan, Haiming; Lee, Jong Seok; Barry, Clifton E.; Wang, Honghai; Zhang, Wenhong; Zhang, Ying.

In: Science, Vol. 333, No. 6049, 16.09.2011, p. 1630-1632.

Research output: Contribution to journalArticle

Shi, W, Zhang, X, Jiang, X, Yuan, H, Lee, JS, Barry, CE, Wang, H, Zhang, W & Zhang, Y 2011, 'Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis', Science, vol. 333, no. 6049, pp. 1630-1632. https://doi.org/10.1126/science.1208813
Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science. 2011 Sep 16;333(6049):1630-1632. https://doi.org/10.1126/science.1208813
Shi, Wanliang ; Zhang, Xuelian ; Jiang, Xin ; Yuan, Haiming ; Lee, Jong Seok ; Barry, Clifton E. ; Wang, Honghai ; Zhang, Wenhong ; Zhang, Ying. / Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. In: Science. 2011 ; Vol. 333, No. 6049. pp. 1630-1632.
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