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 ethionamide (ETH) in Mycobacterium smegmatis and M. bovis. From this observation, it has been anticipated that some of the INH-resistant clinical isolates of M. tuberculosis would carry missense mutations in the same region of the gene. However, few polymorphisms have been identified in this region among 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 M. tuberculosis 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. Interestingly, all the mutations were of the same kind, which substitutes C to T. Among 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 inhA have no particular relationship with the mechanism involved in the resistance of M. tuberculosis to INH and/or ETH. On the other hand, the resistance 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.