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 journalArticlepeer-review

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

ASJC Scopus subject areas

  • General

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