Imidazoles Induce Reactive Oxygen Species inMycobacterium tuberculosisWhich Is Not Associated with Cell Death.
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 toMycobacterium tuberculosis. A marked increase in reactive oxygen species (ROS) was observed within imidazole-treatedM. 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 ofM. 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.
TB Discovery Research, Infectious Disease Research Institute , 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
Heather A
HA
Howell Wescott
TB Discovery Research, Infectious Disease Research Institute , 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
David M
DM
Roberts
TB Discovery Research, Infectious Disease Research Institute , 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
Christian L
CL
Allebach
TB Discovery Research, Infectious Disease Research Institute , 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
Rachel
R
Kokoczka
TB Discovery Research, Infectious Disease Research Institute , 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
Tanya
T
Parish