Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.

Article Details

Citation
Copy to clipboard

Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE 3rd, Wang H, Zhang W, Zhang Y

Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.

Science. 2011 Sep 16;333(6049):1630-2. doi: 10.1126/science.1208813. Epub 2011 Aug 11.

PubMed ID
21835980 [ View in PubMed
]
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 DeltaAla 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.

DrugBank Data that Cites this Article

Drugs