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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Imidazoles Induce Reactive Oxygen Species in Mycobacterium tuberculosis Which Is Not Associated with Cell Death
Heather A Howell Wescott1, David M Roberts1, Christian L Allebach1
1TB Discovery Research, Infectious Disease Research Institute , 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
Abstract:
Azoles are a class of antimicrobial drugs used clinically to treat yeast and fungal infections. Against pathogenic yeast and fungi, azoles act by inhibiting the activity of the cytochrome P450 Cyp51, which is involved in the synthesis of a critical component of the yeast and fungal cell membrane. Azoles have antibacterial activity, including against mycobacteria, but the basis for this activity is not well-understood. We demonstrated that imidazoles are bactericidal to Mycobacterium tuberculosis. A marked increase in reactive oxygen species (ROS) was observed within imidazole-treated M. tuberculosis. The generation of ROS did not appear to be related to the mechanism of killing of imidazoles, as the addition of antioxidants or altered expression of detoxifying enzymes had no effect on growth. We examined the metabolic changes induced by econazole treatment in both wild-type and econazole-resistant mutant strains of M. tuberculosis. Econazole treatment induced changes in carbohydrates, amino acids, and energy metabolism in both strains. Notably, the untreated mutant strain had a metabolic profile similar to the wild-type drug-treated cells, suggesting that adaptation to similar stresses may play a role in econazole resistance.
Insights
Imidazoles kill Mycobacterium tuberculosis by a mechanism independent of reactive oxygen species (ROS). Econazole treatment alters metabolism in M. tuberculosis, with resistant strains showing pre-adapted metabolic profiles.
Area of Science:
- Antimicrobial drug research
- Mycobacterial infections
- Drug resistance mechanisms
Background:
- Azoles are antifungal drugs inhibiting cytochrome P450 Cyp51, crucial for fungal cell membranes.
- Azoles exhibit antibacterial activity against mycobacteria, but the underlying mechanisms remain unclear.
- Understanding azole antibacterial activity is vital for developing new treatments for mycobacterial diseases.
Purpose of the Study:
- To investigate the bactericidal mechanism of imidazoles against Mycobacterium tuberculosis.
- To explore the metabolic alterations induced by econazole in M. tuberculosis.
- To elucidate potential mechanisms of econazole resistance in M. tuberculosis.
Main Methods:
- Treatment of M. tuberculosis with imidazole and econazole.
- Measurement of reactive oxygen species (ROS) generation.
- Analysis of metabolic changes using metabolic profiling.
- Comparison of wild-type and econazole-resistant mutant strains.
Main Results:
- Imidazoles demonstrated bactericidal activity against M. tuberculosis.
- Increased ROS levels were observed in imidazole-treated M. tuberculosis, but ROS were not linked to cell death.
- Econazole treatment induced significant metabolic changes in carbohydrates, amino acids, and energy metabolism.
- Econazole-resistant mutants exhibited metabolic profiles resembling drug-treated wild-type cells.
Conclusions:
- The bactericidal effect of imidazoles on M. tuberculosis is not mediated by ROS.
- Metabolic adaptation to stress may contribute to econazole resistance in M. tuberculosis.
- Further research into azole-drug resistance mechanisms is warranted for effective therapeutic strategies.
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