NADH dehydrogenase defects confer isoniazid resistance and conditional- lethality in Mycobacterium smegmatis

Lynn Miesel, Torin Weisbrod, Jovita A. Marcinkeviciene, Robert Bittman, William R. Jacobs

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2459-2467
Number of pages9
JournalJournal of Bacteriology
Volume180
Issue number9
StatePublished - May 1998

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Mycobacterium smegmatis
NADH Dehydrogenase
Isoniazid
NAD
Mycobacterium tuberculosis
Ethionamide
Phenotype
Malate Dehydrogenase
Mutation
Mycobacterium Infections
Pharmaceutical Preparations
Enzymes
Genes

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Immunology

Cite this

NADH dehydrogenase defects confer isoniazid resistance and conditional- lethality in Mycobacterium smegmatis. / Miesel, Lynn; Weisbrod, Torin; Marcinkeviciene, Jovita A.; Bittman, Robert; Jacobs, William R.

In: Journal of Bacteriology, Vol. 180, No. 9, 05.1998, p. 2459-2467.

Research output: Contribution to journalArticle

Miesel, L, Weisbrod, T, Marcinkeviciene, JA, Bittman, R & Jacobs, WR 1998, 'NADH dehydrogenase defects confer isoniazid resistance and conditional- lethality in Mycobacterium smegmatis', Journal of Bacteriology, vol. 180, no. 9, pp. 2459-2467.
Miesel, Lynn ; Weisbrod, Torin ; Marcinkeviciene, Jovita A. ; Bittman, Robert ; Jacobs, William R. / NADH dehydrogenase defects confer isoniazid resistance and conditional- lethality in Mycobacterium smegmatis. In: Journal of Bacteriology. 1998 ; Vol. 180, No. 9. pp. 2459-2467.
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