TY - JOUR
T1 - NADH dehydrogenase defects confer isoniazid resistance and conditional- lethality in Mycobacterium smegmatis
AU - Miesel, Lynn
AU - Weisbrod, Torin R.
AU - Marcinkeviciene, Jovita A.
AU - Bittman, Robert
AU - Jacobs, William R.
PY - 1998/5
Y1 - 1998/5
N2 - Isoniazid (INH) is a highly effective drug used in the treatment and prophylaxis of Mycobacterium tuberculosis infections. Resistance to INH in clinical isolates has been correlated with mutations in the inhA, katG, and ahpC genes. In this report, we describe a new mechanism for INH resistance in Mycobacterium smegmatis. Mutations that reduce NADH dehydrogenase activity (Ndh; type II) cause multiple phenotypes, including (i) coresistance to INH and a related drug, ethionamide; (ii) thermosensitive lethality; and (iii) auxotrophy. These phenotypes are corrected by expression of one of two enzymes: NADH dehydrogenase and the NADH-dependent malate dehydrogenase of the M. tuberculosis complex. The genetic data presented here indicate that defects in NADH oxidation cause all of the mutant traits and that an increase in the NADH/NAD+ ratio confers INH resistance.
AB - Isoniazid (INH) is a highly effective drug used in the treatment and prophylaxis of Mycobacterium tuberculosis infections. Resistance to INH in clinical isolates has been correlated with mutations in the inhA, katG, and ahpC genes. In this report, we describe a new mechanism for INH resistance in Mycobacterium smegmatis. Mutations that reduce NADH dehydrogenase activity (Ndh; type II) cause multiple phenotypes, including (i) coresistance to INH and a related drug, ethionamide; (ii) thermosensitive lethality; and (iii) auxotrophy. These phenotypes are corrected by expression of one of two enzymes: NADH dehydrogenase and the NADH-dependent malate dehydrogenase of the M. tuberculosis complex. The genetic data presented here indicate that defects in NADH oxidation cause all of the mutant traits and that an increase in the NADH/NAD+ ratio confers INH resistance.
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U2 - 10.1128/jb.180.9.2459-2467.1998
DO - 10.1128/jb.180.9.2459-2467.1998
M3 - Article
C2 - 9573199
AN - SCOPUS:0031980127
SN - 0021-9193
VL - 180
SP - 2459
EP - 2467
JO - Journal of Bacteriology
JF - Journal of Bacteriology
IS - 9
ER -