MOLECULAR-BASIS FOR THE EXQUISITE SENSITIVITY OF MYCOBACTERIUM-TUBERCULOSIS TO ISONIAZID

The exceptional sensitivity of Mycobacterium tuberculosis to isonicoti nic acid hydrazide (INH) lacks satisfactory definition. M. tuberculosi s is a natural mutant in oxyR, a central regulator of peroxide stress response, The ahpC gene, which encodes a critical subunit of alkyl hyd roperoxide reductase, is one of the targets usually controlled by oxyR in bacteria, Unlike in mycobacterial species less susceptible to INH, the expression of ahpC was below detection limits at the protein leve l in INH-sensitive M. tuberculosis and Mycobacterium bovis strains, In contrast, AhpC was detected in several series of isogenic INH-resista nt (INHr) derivatives. In a demonstration of the critical role of ahpC in sensitivity to MH, insertional inactivation of ahpC on the chromos ome of Mycobacterium smegmatis, a species naturally insensitive to INH , dramatically increased its susceptibility to this compound, These fi ndings suggest that AhpC counteracts the action of INH and that the le vels of its expression may govern the intrinsic susceptibility of myco bacteria to this front-line antituberculosis drug.