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

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 sug...

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Autores principales:	Nicholas A. Dillon, Nicholas D. Peterson, Heather A. Feaga, Kenneth C. Keiler, Anthony D. Baughn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4da58e057f364be4a086d7bff82b17a5
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spelling	oai:doaj.org-article:4da58e057f364be4a086d7bff82b17a52021-12-02T15:04:56ZAnti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA10.1038/s41598-017-06415-52045-2322https://doaj.org/article/4da58e057f364be4a086d7bff82b17a52017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06415-5https://doaj.org/toc/2045-2322Abstract 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.Nicholas A. DillonNicholas D. PetersonHeather A. FeagaKenneth C. KeilerAnthony D. BaughnNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicholas A. Dillon Nicholas D. Peterson Heather A. Feaga Kenneth C. Keiler Anthony D. Baughn Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
description	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.
format	article
author	Nicholas A. Dillon Nicholas D. Peterson Heather A. Feaga Kenneth C. Keiler Anthony D. Baughn
author_facet	Nicholas A. Dillon Nicholas D. Peterson Heather A. Feaga Kenneth C. Keiler Anthony D. Baughn
author_sort	Nicholas A. Dillon
title	Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
title_short	Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
title_full	Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
title_fullStr	Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
title_full_unstemmed	Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
title_sort	anti-tubercular activity of pyrazinamide is independent of trans-translation and rpsa
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4da58e057f364be4a086d7bff82b17a5
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Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA

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