TY - JOUR
T1 - Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis
AU - Vilchèze, Catherine
AU - Av-Gay, Yossef
AU - Attarian, Rodgoun
AU - Liu, Zhen
AU - Hazbón, Manzour H.
AU - Colangeli, Roberto
AU - Chen, Bing
AU - Liu, Weijun
AU - Alland, David
AU - Sacchettini, James C.
AU - Jacobs, William R.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
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U2 - 10.1111/j.1365-2958.2008.06365.x
DO - 10.1111/j.1365-2958.2008.06365.x
M3 - Article
C2 - 18651841
AN - SCOPUS:49249132882
SN - 0950-382X
VL - 69
SP - 1316
EP - 1329
JO - Molecular Microbiology
JF - Molecular Microbiology
IS - 5
ER -