Open AccessAnti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA
Author(s) -
Nicholas Dillon,
Nicholas Peterson,
Heather A. Feaga,
Kenneth C. Keiler,
Anthony D. Baughn
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-06415-5
Subject(s) - pyrazinamide , ribosome , translation (biology) , mycobacterium tuberculosis , protein biosynthesis , tuberculosis , biology , computational biology , genetics , microbiology and biotechnology , rna , medicine , gene , messenger rna , pathology
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 .