Belenky P, et al., Fungicidal Drugs Induce a Common Oxidative-Damage Cellular Death Pathway. Cell Reports, 2013. 3(2): 350-358.
Metabolon results led to:
- Identification of a common cell-killing mechanism from distinct classes of antifungals and thus, potential new targets
Key metabolomic observations:
- Dramatic changes in glucose and other primary carbon sources
- Reduction in fermentative carbon sources (glycerol and 2,3-butandiol)
- An increase in pyruvate and TCA cycle intermediates
There is a growing need for improved antifungals due to the persistent morbidity and mortality rates and the growing population of immunocompromised patients. Thus, investigators in James Collins laboratory sought to develop a greater mechanistic understanding of antifungal agents. Using a systems biology approach, they examined S. cerevisiae and C. albicans in response to treatment with drugs from three different classes (amphotericin, miconazole, and ciclopirox). Metabolomics clarified and strengthened gene expression findings by showing that drug treatment caused yeast to channel monosacharides into polysaccharide synthesis, switch fermentation off, and concomitantly engage mitochondrial respiration to induce toxic ROS. ROS production is a natural stress response, however, with these antifiungals, the pathway is overactivated, ultimately destroying the cell. Thus, despite the drugs having different primary modes of action, a common oxidative-damage cellular death pathway was elucidated. Hence, finding ways to induce these pathways may lead to more efficacious and broader-spectrum antifungal agents.