BIOCHEMICAL AND GENETIC DATA SUGGEST THAT INHA IS NOT THE PRIMARY TARGET FOR ACTIVATED ISONIAZID IN MYCOBACTERIUM-TUBERCULOSIS

An examination of the pattern of lipid biosynthetic responses to isoni azid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium s megmatis suggests that the mode of action of activated INH differs bet ween these 2 organisms, Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the sa me construct failed to confer resistance upon M. tuberculosis, The inh A region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was no t sufficient to impart INH resistance to the level of the parent strai n on sensitive M. tuberculosis, These putative mutant promoter element s appear to elevate expression levels of gene fusion reporter construc ts, suggesting some noncausal connection between the observed mutation s and the lipid metabolism of drug-resistant organisms, These results suggest that InhA is not the major target for activated INH in M. tube rculosis.