Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis

Catherine Vilchèze, Yossef Av-Gay, Rodgoun Attarian, Zhen Liu, Manzour H. Hazbón, Roberto Colangeli, Bing Chen, Weijun Liu, David Alland, James C. Sacchettini, William R. Jacobs

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Abstract

Spontaneous mutants of Mycobacterium tuberculosis that were resistant to the anti-tuberculosis drugs ethionamide and isoniazid were isolated and found to map to mshA, a gene encoding the first enzyme involved in the biosynthesis of mycothiol, a major low-molecular-weight thiol in M. tuberculosis. Seven independent missense or frameshift mutations within mshA were identified and characterized. Precise null deletion mutations of the mshA gene were generated by specialized transduction in three different strains of M. tuberculosis. The mshA deletion mutants were defective in mycothiol biosynthesis, were only ethionamide-resistant and required catalase to grow. Biochemical studies suggested that the mechanism of ethionamide resistance in mshA mutants was likely due to a defect in ethionamide activation. In vivo, a mycothiol-deficient strain grew normally in immunodeficient mice, but was slightly defective for growth in immunocompetent mice. Mutations in mshA demonstrate the non-essentiality of mycothiol for growth in vitro and in vivo, and provide a novel mechanism of ethionamide resistance in M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)1316-1329
Number of pages14
JournalMolecular Microbiology
Volume69
Issue number5
DOIs
StatePublished - Sep 1 2008

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ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

Vilchèze, C., Av-Gay, Y., Attarian, R., Liu, Z., Hazbón, M. H., Colangeli, R., Chen, B., Liu, W., Alland, D., Sacchettini, J. C., & Jacobs, W. R. (2008). Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Molecular Microbiology, 69(5), 1316-1329. https://doi.org/10.1111/j.1365-2958.2008.06365.x