Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA

Drug-resistant tuberculosis poses a significant problem for treatment. The mechanisms of resistance to the front-line drug isoniazid (INN) are complex and can be mediated by katG, inhA and other unknown genes. To identify the percentage of INH-resistant strains with no katG or inhA mutation, this study characterized a panel of 28 clinical isolates of Mycobacterium tuberculosis and five mutants derived from H37Rv resistant to INH. Seventeen of 33 resistant strains (51%) had katG mutations with 12 of the 1 7 strains having the most common KatG Ser315Thr mutation. Three of the 17 strains with the KatG 315 mutation had an additional mutation in the inhA promoter and were resistant to a high level of INH. Seventeen of the 33 INH-resistant strains (51%) had inhA mutations. The most common inhA promoter mutation was -15C -> T and was present in 13 of the 17 inhA mutations. This promoter mutation occurred alone without katG mutations and was associated with a low level of INH and ethionamide resistance. However, other inhA mutations were associated with katG mutations. No mutations were found in the ndh gene. Three of 33 strains (9%) had no mutations in katG, inhA or ndh, indicating that their resistance was due to a new mechanism of resistance. Detection of the KatG Ser315Thr mutation and the -15C -> T inhA mutation accounted for 76% (25/33) of the INH-resistant strains and should be useful for rapid detection of INH-resistant strains by molecular tests.