Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA

Nicholas A. Dillon, Nicholas D. Peterson, Heather A. Feaga, Kenneth Charles Keiler, Anthony D. Baughn

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Pyrazinamide (PZA) is a first line anti-tubercular drug for which the mechanism of action remains unresolved. Recently, it was proposed that the active form of PZA, pyrazinoic acid (POA), disrupts the ribosome rescue process of trans-translation in Mycobacterium tuberculosis. This model suggested that POA binds within the carboxy-terminal domain of ribosomal protein S1 (RpsA) and inhibits trans-translation leading to accumulation of stalled ribosomes. Here, we demonstrate that M. tuberculosis RpsA interacts with single stranded RNA, but not with POA. Further, we show that an rpsA polymorphism previously identified in a PZA resistant strain does not confer PZA resistance when reconstructed in a laboratory strain. Finally, by utilizing an in vitro trans-translation assay with purified M. tuberculosis ribosomes we find that an interfering oligonucleotide can inhibit trans-translation, yet POA does not inhibit trans-translation. Based on these findings, we conclude that the action of PZA is entirely independent of RpsA and trans-translation in M. tuberculosis.

Original languageEnglish (US)
Article number6135
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Pyrazinamide
Mycobacterium tuberculosis
Ribosomes
Oligonucleotides
RNA
pyrazinoic acid
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • General

Cite this

Dillon, Nicholas A. ; Peterson, Nicholas D. ; Feaga, Heather A. ; Keiler, Kenneth Charles ; Baughn, Anthony D. / Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA. / Dillon, Nicholas A.; Peterson, Nicholas D.; Feaga, Heather A.; Keiler, Kenneth Charles; Baughn, Anthony D.

In: Scientific reports, Vol. 7, No. 1, 6135, 01.12.2017.

Research output: Contribution to journalArticle

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