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Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis
Author(s) -
Ando Hiroki,
Kitao Tomoe,
MiyoshiAkiyama Tohru,
Kato Seiya,
Mori Toru,
Kirikae Teruo
Publication year - 2011
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2011.07547.x
Subject(s) - inha , isoniazid , mycobacterium tuberculosis , biology , microbiology and biotechnology , mutation , tuberculosis , drug resistance , genetics , gene , medicine , pathology
Summary Isoniazid (INH) is a key agent in the treatment of tuberculosis. In Mycobacterium tuberculosis , INH is converted to its active form by KatG, a catalase‐peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA–katG and fabG1–inhA in 108 INH‐resistant (INH r ) and 51 INH‐susceptible (INH s ) isolates, and found three mutations in the furA–katG intergenic region (Int g‐7a , Int a‐10c and Int g‐12a ) in four of 108 INH r isolates (4%), and the furA c41t mutation with an amino acid substitution in 18 INH r isolates (17%). These mutations were not found in any of 51 INH s isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Int g‐7a , Int a‐10c and Int g‐12a single mutations in the furA–katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furA c41t mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA–katG intergenic region play a role in this resistance mechanism.