Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis

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 (INHr) and 51 INH-susceptible (INHs) isolates, and found three mutations in the furA-katG intergenic region (Intg-⁷a, Inta-¹⁰c and Intg-¹²a) in four of 108 INHr isolates (4%), and the furAc⁴¹t mutation with an amino acid substitution in 18 INHr isolates (17%). These mutations were not found in any of 51 INHs isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Intg-⁷a, Inta-¹⁰c and Intg-¹²a single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furAc⁴¹t 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.