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Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis
D R Sherman1, K Mdluli, M J Hickey
1Laboratory of Tuberculosis and Molecular Microbiology, PathoGenesis Corporation, Seattle, Washington 98119, USA.
Science (New York, N.Y.)
|June 14, 1996
Summary
Mutations reducing isoniazid drug effectiveness in Mycobacterium tuberculosis are common. Isoniazid-resistant bacteria survive by increasing levels of another protective protein, alkyl hydroperoxidase (AhpC).
Area of Science:
- Microbiology
- Drug Resistance
- Biochemistry
Background:
- Isoniazid is a primary drug for treating Mycobacterium tuberculosis infections.
- Mutations in KatG catalase-peroxidase activity are a key mechanism of isoniazid resistance.
- The loss of KatG activity in clinical isolates was paradoxical due to KatG's importance for bacterial survival.
Purpose of the Study:
- To investigate the compensatory mechanisms in isoniazid-resistant Mycobacterium tuberculosis lacking KatG activity.
- To understand how Mycobacterium tuberculosis survives during infection despite mutations conferring isoniazid resistance.
Main Methods:
- Analysis of clinical isolates of Mycobacterium tuberculosis.
- Assessing the role of KatG and alkyl hydroperoxidase (AhpC) in protecting against organic peroxides.
- Investigating gene expression changes in isoniazid-resistant mutants.
Main Results:
- Expression of either KatG or AhpC provided protection against organic peroxides.
- Isoniazid-resistant KatG mutants showed hyperexpression of AhpC.
- This suggests AhpC compensates for the loss of KatG function.
Conclusions:
- Mycobacterium tuberculosis employs compensatory mechanisms to survive during infection.
- Hyperexpression of alkyl hydroperoxidase (AhpC) allows isoniazid-resistant strains to overcome the loss of KatG catalase-peroxidase activity.
- AhpC plays a crucial role in the survival of isoniazid-resistant Mycobacterium tuberculosis.