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Mechanisms for isoniazid action and resistance
L Miesel1, D A Rozwarski, J C Sacchettini
1Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
Novartis Foundation Symposium
|February 9, 1999
Summary
Isoniazid resistance in tuberculosis can stem from mutations affecting NADH levels. This study in Mycobacterium smegmatis reveals how altered NADH dehydrogenase function impacts drug efficacy.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Resistance Studies
Background:
- Isoniazid is a primary drug for tuberculosis treatment, targeting the InhA enzyme.
- Drug resistance mechanisms, including InhA overexpression or mutations, are prevalent in clinical isolates.
- The KatG enzyme is a common factor in isoniazid resistance.
Purpose of the Study:
- To investigate novel mechanisms of isoniazid resistance in Mycobacterium smegmatis.
- To explore the role of NADH dehydrogenase (Ndh) in conferring resistance.
- To assess the potential relevance of these findings to Mycobacterium tuberculosis.
Main Methods:
- Genetic studies in Mycobacterium smegmatis.
- Analysis of mutations in NADH dehydrogenase (Ndh).
- Examination of intracellular NADH/NAD+ ratios.
- Biochemical assays to assess enzyme activity and drug-target interactions.
Main Results:
- Mutations in ndh confer isoniazid resistance by altering NADH oxidation rates.
- Defects in Ndh lead to an increased intracellular NADH/NAD+ ratio.
- Elevated NADH levels may interfere with the formation or binding of the inhibitory isoniazid-NAD adduct to InhA.
Conclusions:
- NADH dehydrogenase defects represent a significant mechanism for isoniazid resistance in M. smegmatis.
- The findings suggest a conserved resistance mechanism that may also operate in Mycobacterium tuberculosis.
- Understanding these pathways is crucial for developing strategies to overcome drug resistance in tuberculosis.