AHPC, A GENE INVOLVED IN ISONIAZID RESISTANCE OF THE MYCOBACTERIUM-TUBERCULOSIS COMPLEX

A gene conferring low-level isoniazid (INH) resistance on Mycobacteriu m smegmatis was isolated from a cosmid library of the genome of an INH -resistant Mycobacterium bovis strain. The gene had good homology with abpC, the product of which is a subunit of alkyl hydroperoxide reduct ase, and also with a family of thiol-specific antioxidant enzymes. A m utation was found in the promoter upon comparison with the equivalent DNA sequence from the INH-sensitive parent strain. Promoter sequences from other INH-sensitive and INH-resistant M. bovis and Mycobacterium tuberculosis strains were sequenced and the mutation was found only in the lNH-resistant strains. An INH-resistant M. tuberculosis strain al so had an additional mutation in the promoter region. The wild-type pr omoter and promoters with one and two mutations were ligated into a re porter plasmid containing the lacZ gene. The presence of the first mut ation resulted in a sixfold induction of beta-galactosidase activity, and the presence of both mutations caused a 10-fold induction. Increas ed expression of AhpC may account for some of the INH resistance of st rains of the M. tuberculosis complex.