Exclusive mutations related to isoniazid and ethionamide resistance among Mycobacterium tuberculosis isolates from Korea

SETTING: The single base change at the 94th codon of inhA has been referred to as the event that confers resistance on the drugs isoniazid (INH) and e thionamide (ETH) in Mycobacterium smegmatis and M. bovis. From this observa tion, it has been anticipated that some of the INH-resistant clinical isola tes of M. tuberculosis would carry missense mutations in the same region of the gene. However, few polymorphisms have been identified in this region a mong INH-resistant isolates. OBJECTIVE: To understand the molecular basis for M. tuberculosis resistance to INH and ETH. DESIGN: The sequence polymorphism at the 94th codon of inhA among IM. tuber culosis isolates from Korea was analyzed by polymerase chain reaction (PCR) cloning and sequence analysis. RESULTS: No nucleotide change at the 94th codon of inhA was detected in any of the 24 INH-resistant isolates analyzed in this study. On the other hand , a point mutation was found exclusively at the regulatory region flanking a putative ribosome-binding site of the inhA locus in 14 isolates. Interest ingly, all the mutations were of the same kind, which substitutes C to T Am ong 14 isolates, 12 were resistant to INH as well as to ETH, while two were resistant to INH only. DISCUSSION: It seems that mutations previously found at the 94th codon of i nhA have no particular relationship with the mechanism involved in the resi stance of M. tuberculosis to INH and/or ETH. On the other hand, the resista nce mechanism of M. tuberculosis to INH/ETH may involve an altered level of InhA, an expression which may have been influenced by the sequence change in the regulatory region of the inhA locus.