Identification of InhA

The enzymatic target of isoniazid was identified from a genetic study with Mycobacterium smegmatis in which isoniazid-resistant mutants that are co-resistant to a structurally related drug, ethionamide, were isolated (Fig. 1; Banerjee et al 1994). This genetic approach was based upon the idea that isoniazid and ethionamide inhibit a common target enzyme such that resistance to both drugs can only occur by an alteration in that enzyme target. A M. smegmatis mutant resistant to both drugs was found to have a mutation in inhA which caused a serine to alanine substitution at position 94 in the InhA enzyme. This mutation was also found in an isoniazid-resistant isolate of Mycobacterium bovis, indicating that the target is conserved in members of the M. tuberculosis complex and that resistance can occur by the same mechanisms (Wilson et al 1995). Allelic exchange studies in M. smegmatis showed that the inhA substitution is

Isoniazid O^NHNH

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