MYCOBACTERIUM-TUBERCULOSIS IS A NATURAL MUTANT WITH AN INACTIVATED OXIDATIVE-STRESS REGULATORY GENE - IMPLICATIONS FOR SENSITIVITY TO ISONIAZID

The systems participating in detoxification of reactive oxygen interme diates in Mycobacterium tuberculosis are believed to play a dual role in the biology of this highly adapted human pathogen: (i) they may con tribute to the survival of this bacterium in the host; and (ii) altera tions in the gene encoding catalase/peroxidase have been linked to thi s organism's resistance to the front-line antituberculosis drug isonia zid. These relationships prompted us to extend investigations of the o xidative-stress-response systems in M. tuberculosis by analysing the a lkyl hydroperoxide reductase gene ahpC and its putative regulator oxyR . Surprisingly, the oxyR gene was found to be inactivated by multiple lesions in M. tuberculosis H37Rv. These alterations were observed in a ll M. tuberculosis strains tested, and in members of the M. tuberculos is complex: Mycobacterium bovis BCG, Mycobacterium africanum, and Myco bacterium microti. The corresponding region carrying these genes in My cobacterium leprae, an organism not sensitive to isoniazid, has a comp lete oxyR gene divergently transcribed from ahpC. An increase in minim al inhibitory concentration for isoniazid was observed upon transforma tion of M. tuberculosis H37Rv with cosmids carrying the oxyR-ahpC regi on of M. leprae. In keeping with the observed inactivation of oxyR, tr anscriptional activity of the corresponding region in M. tuberculosis was an order of magnitude lower than that of the oxyR gene from M. lep rae. While the loss of this putative regulator of oxidative-stress res ponse in M. tuberculosis is paradoxical considering the fact that surv ival in host macrophages is regarded as a critical feature of this pat hogen, it offers a partial explanation for the exquisite sensitivity o f M. tuberculosis to isoniazid.