The extreme sensitivity of Mycobacterium tuberculosis to the front-line antituberculosis drug isoniazid


Mycobacterium tuberculosis is a natural mutant in oxyR, a close homolog of the central regulator of peroxide stress response in enteric bacteria. Inactivation of oxyR is specific for M. tuberculosis and other members of the M. tuberculosis complex. This phenomenon appears as a paradox due to the ability of this organism to parasitize host macrophages, in which the ingested organisms are likely to be exposed to reactive oxygen intermediates. However, the surprising finding that M. tuberculosis has multiple deletions, nonsense and frameshift mutations in oxyR may help explain the exceptionally high sensitivity of M. tuberculosis to the potent antituberculosis agent isoniazid. One of the genes affected by oxyR lesions, ahpC (encoding an alkylhydroperoxide reductase) may determine the intrinsic sensitivity of mycobacteria to isoniazid.

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Deretic, V., Pagán-Ramos, E., Zhang, Y. et al. The extreme sensitivity of Mycobacterium tuberculosis to the front-line antituberculosis drug isoniazid. Nat Biotechnol 14, 1557–1561 (1996).

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