Science. 2011 Sep 16;333(6049):1630-2. Epub 2011 Aug 11.

Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.

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

Source

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

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.

Comment in

Science. 2011 Sep 16;333(6049):1583-4.

PMID:: 21835980; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

AI44063/AI/NIAID NIH HHS/United States

LinkOut - more resources

Full Text Sources

Other Literature Sources

See the articles identified as outstanding by F1000's Faculty of 10,000 renowned researchers and clinicians. - F1000

Molecular Biology Databases

PYRAZINAMIDE - HSDB

Supplemental Content

Save items

Related citations in PubMed

Microbiology. Pyrazinamide--old TB drug finds new target. [Science. 2011]
Microbiology. Pyrazinamide--old TB drug finds new target.
Cole ST. Science. 2011 Sep 16; 333(6049):1583-4.
The pncA gene from naturally pyrazinamide-resistant Mycobacterium avium encodes pyrazinamidase and confers pyrazinamide susceptibility to resistant M. tuberculosis complex organisms. [Microbiology. 1997]
The pncA gene from naturally pyrazinamide-resistant Mycobacterium avium encodes pyrazinamidase and confers pyrazinamide susceptibility to resistant M. tuberculosis complex organisms.
Sun Z, Scorpio A, Zhang Y. Microbiology. 1997 Oct; 143 ( Pt 10):3367-73.
pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada. [Antimicrob Agents Chemother. 2...]
pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada.
Cheng SJ, Thibert L, Sanchez T, Heifets L, Zhang Y. Antimicrob Agents Chemother. 2000 Mar; 44(3):528-32.
Review The paradox of pyrazinamide: an update on the molecular mechanisms of pyrazinamide resistance in Mycobacteria. [J Commun Dis. 2006]
Review The paradox of pyrazinamide: an update on the molecular mechanisms of pyrazinamide resistance in Mycobacteria.
Singh P, Mishra AK, Malonia SK, Chauhan DS, Sharma VD, Venkatesan K, Katoch VM. J Commun Dis. 2006 Mar; 38(3):288-98.
Review The curious characteristics of pyrazinamide: a review. [Int J Tuberc Lung Dis. 2003]
Review The curious characteristics of pyrazinamide: a review.
Zhang Y, Mitchison D. Int J Tuberc Lung Dis. 2003 Jan; 7(1):6-21.

See reviews... See all...

Cited by 2 PubMed Central articles

MSMEG_2731, an Uncharacterized Nucleic Acid Binding Protein from Mycobacterium smegmatis, Physically Interacts with RPS1. [PLoS One. 2012]
MSMEG_2731, an Uncharacterized Nucleic Acid Binding Protein from Mycobacterium smegmatis, Physically Interacts with RPS1.
Yang M, Chen Y, Zhou Y, Wang L, Zhang H, Bi LJ, Zhang XE. PLoS One. 2012; 7(5):e36666. Epub 2012 May 9.
Viewpoint: challenges and opportunities in tuberculosis research. [J Infect Dis. 2012]
Viewpoint: challenges and opportunities in tuberculosis research.
Kim PS, Makhene M, Sizemore C, Hafner R. J Infect Dis. 2012 May; 205 Suppl 2:S347-52. Epub 2012 Mar 22.

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Gene
Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
Gene (GeneRIF)
Gene records that have the current articles as Reference into Function citations (GeneRIFs). NLM staff reviewing the literature while indexing MEDLINE add GeneRIFs manually.
Nucleotide (Weighted)
Nucleotide records associated with the current articles through the Gene database. These are the related sequences on the Gene record that are added manually by NCBI.
Protein (RefSeq)
NCBI protein Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Protein (Weighted)
Protein records associated with the current articles through related Gene database records. These are the related sequences on the Gene record that are added manually by NCBI.
Protein Clusters
Clusters of related proteins from the Protein Clusters database that cite the current articles. Sources of references in Protein Clusters include the associated Gene and Conserved Domain records as well as NCBI added citations.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Taxonomy via GenBank
Taxonomy records associated with the current articles through taxonomic information on related molecular database records (Nucleotide, Protein, Gene, SNP, Structure).
GEO Profiles
Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.
Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.
Science. 2011 Sep 16 ;333(6049):1630-2. Epub 2011 Aug 11 .

PubMed
A laboratory-based evaluation of the BioStar Optical ImmunoAssay point-of-care t...
A laboratory-based evaluation of the BioStar Optical ImmunoAssay point-of-care test for diagnosing Neisseria gonorrhoeae infection.
J Med Microbiol. 2011 Dec ;60(Pt 12):1779-81. Epub 2011 Aug 11 .

PubMed
Increased PKA signaling disrupts recognition memory and spatial memory: role in ...
Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease.
Hum Mol Genet. 2011 Nov 1 ;20(21):4232-47. Epub 2011 Aug 11 .

PubMed
An unusual gum lesion with a positive pregnancy test.
An unusual gum lesion with a positive pregnancy test.
BMJ. 2011 Aug 11 ;343:d5009. doi: 10.1136/bmj.d5009.

PubMed
Pulmonary lymphangioleiomyomatosis and steroid receptors. An immunocytochemical ...
Pulmonary lymphangioleiomyomatosis and steroid receptors. An immunocytochemical study.
Am J Clin Pathol. 1990 May ;93(5):609-14.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: