Mechanisms for isoniazid action and resistance

Lynn Miesel, Denise A. Rozwarski, James C. Sacchettini, William R. Jacobs

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Isoniazid is the most widely used antituberculosis drug. Genetic studies in Mycobacterium smegmatis identified the inhA-encoded, NADH-dependent enoyl acyl carrier protein reductase as the primary target for this drug. A reactive form of isoniazid inhibits InhA by reacting with the NAD(H) cofactor bound to the enzyme active site forming a covalent adduct (isonicotinic acyl NADH) that is apt to bind with high affinity. Resistance can occur by increased expression of InhA or by mutations that lower the enzyme's affinity to NADH. Both of these resistance mechanisms are observed in 30% of clinical tuberculosis isolates. Mutation in katG, which encodes catalase peroxidase, is the most common source for resistance. Another mechanism for isoniazid resistance, in M. smegmatis, occurs by defects in NADH dehydrogenase (Ndh) of the respiratory chain. Genetic data indicated that ndh mutations confer resistance by lowering the rate of NADH oxidation and increasing the intracellular NADH/NAD+ ratio. An increased amount of NADH may prevent formation of isonicotinic acyl NADH or may promote displacement of the isonicotinic acyl NADH from InhA. While our studies have identified this mechanism in M. smegmatis, results reported in early literature lead us to believe that it can occur in Mycobacterium tuberculosis.

Original languageEnglish (US)
Pages (from-to)209-221
Number of pages13
JournalNovartis Foundation Symposium
Issue number217
StatePublished - Dec 1 1998

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Isoniazid
NAD
Mycobacterium smegmatis
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
Mutation
NADH Dehydrogenase
Enzymes
Electron Transport
Mycobacterium tuberculosis
Pharmaceutical Preparations
Catalase
Peroxidase
Catalytic Domain
Tuberculosis
isonicotinyl-NAD

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Miesel, L., Rozwarski, D. A., Sacchettini, J. C., & Jacobs, W. R. (1998). Mechanisms for isoniazid action and resistance. Novartis Foundation Symposium, (217), 209-221.

Mechanisms for isoniazid action and resistance. / Miesel, Lynn; Rozwarski, Denise A.; Sacchettini, James C.; Jacobs, William R.

In: Novartis Foundation Symposium, No. 217, 01.12.1998, p. 209-221.

Research output: Contribution to journalArticle

Miesel, L, Rozwarski, DA, Sacchettini, JC & Jacobs, WR 1998, 'Mechanisms for isoniazid action and resistance', Novartis Foundation Symposium, no. 217, pp. 209-221.
Miesel L, Rozwarski DA, Sacchettini JC, Jacobs WR. Mechanisms for isoniazid action and resistance. Novartis Foundation Symposium. 1998 Dec 1;(217):209-221.
Miesel, Lynn ; Rozwarski, Denise A. ; Sacchettini, James C. ; Jacobs, William R. / Mechanisms for isoniazid action and resistance. In: Novartis Foundation Symposium. 1998 ; No. 217. pp. 209-221.
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