Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria

Catherine Vilchèze, Torin R. Weisbrod, Bing Chen, Laurent Kremer, Manzour H. Hazbón, Feng Wang, David Alland, James C. Sacchettini, William R. Jacobs

Research output: Contribution to journalArticle

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Abstract

The front-line antituberculosis drug isoniazid (INH) and the related drug ethionamide (ETH) are prodrugs that upon activation inhibit the synthesis of mycolic acids, leading to bactericidal activity. Coresistance to INH and ETH can be mediated by dominant mutations in the target gene inhA, encoding an enoyl-ACP reductase, or by recessive mutations in ndh, encoding a type II NADH dehydrogenase (NdhII). To address the mechanism of resistance mediated by the latter, we have isolated novel ndh mutants of Mycobacterium smegmatis and Mycobacterium bovis BCG. The M. smegmatis ndh mutants were highly resistant to INH and ETH, while the M. bovis BCG mutants had low-level resistance to INH and ETH. All mutants had defects in NdhII activity resulting in an increase in intracellular NADH/NAD+ ratios. Increasing NADH levels were shown to protect InhA against inhibition by the INH-NAD adduct formed upon INH activation. We conclude that ndh mutations mediate a novel mechanism of resistance by increasing the NADH cellular concentration, which competitively inhibits the binding of INH-NAD or ETH-NAD adduct to InhA.

Original languageEnglish (US)
Pages (from-to)708-720
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume49
Issue number2
DOIs
StatePublished - Feb 2005

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Ethionamide
Isoniazid
Mycobacterium
NAD
Mycobacterium bovis
Mycobacterium smegmatis
Mutation
Mycolic Acids
Prodrugs
Pharmaceutical Preparations
Oxidoreductases
Genes

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. / Vilchèze, Catherine; Weisbrod, Torin R.; Chen, Bing; Kremer, Laurent; Hazbón, Manzour H.; Wang, Feng; Alland, David; Sacchettini, James C.; Jacobs, William R.

In: Antimicrobial Agents and Chemotherapy, Vol. 49, No. 2, 02.2005, p. 708-720.

Research output: Contribution to journalArticle

Vilchèze, Catherine ; Weisbrod, Torin R. ; Chen, Bing ; Kremer, Laurent ; Hazbón, Manzour H. ; Wang, Feng ; Alland, David ; Sacchettini, James C. ; Jacobs, William R. / Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. In: Antimicrobial Agents and Chemotherapy. 2005 ; Vol. 49, No. 2. pp. 708-720.
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