Mechanism of Antifungal Activity of Terpenoid Phenols Resembles Calcium Stress and Inhibition of the TOR Pathway

Abstract

Terpenoid phenols, including carvacrol, are components of oregano and other plant essential oils that exhibit potent antifungal activity against a wide range of pathogens, including Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa. To gain a mechanistic view of the cellular response to terpenoid phenols, we used Saccharomyces cerevisiae as a model organism and monitored temporal changes in metabolic activity, cytosolic and vacuolar pH, and Ca 2؉ transients. Using a panel of related compounds, we observed dosedependent Ca 2؉ bursts that correlated with antifungal efficacy. Changes in pH were long lasting and followed the Ca 2؉ transients. A vma mutant lacking functional vacuolar H ؉ -ATPase (V-ATPase) and defective in ion homeostasis was hypersensitive to carvacrol toxicity, consistent with a role for ionic disruptions in mediating cell death. Genomic profiling within 15 min of exposure revealed a robust transcriptional response to carvacrol, closely resembling that of calcium stress. Genes involved in alternate metabolic and energy pathways, stress response, autophagy, and drug efflux were prominently upregulated, whereas repressed genes mediated ribosome biogenesis and RNA metabolism. These responses were strongly reminiscent of the effects of rapamycin, the inhibitor of the TOR pathway of nutrient sensing. The results point to the activation of specific signaling pathways downstream of cellular interaction with carvacrol rather than a nonspecific lesion of membranes, as has been previously proposed.While the medicinal properties of herbs have been recognized since ancient times, there has been a resurgence of interest in the antimicrobial properties of botanical extracts. Essential oils have been amply documented to kill a wide range of pathogenic fungi and bacteria, such as Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa, including their drug-resistant variants (6,10,21,22). Of the herbal extracts tested, essential oils derived from the genus Oreganum were among the most effective, with an in vitro MIC of 500 ppm against C. albicans (27). Major components of oregano extract, which include the terpenoid phenols carvacrol, thymol, and eugenol, have potent antifungal activity of their own (4, 23, 24). Terpenoid phenols have been shown to be efficacious not only on planktonic cells but also on biofilms of Candida albicans that are resistant to many antifungal drugs. Carvacrol demonstrated the strongest antifungal activity against Candida albicans biofilms, with a MIC of Ͻ0.03% (9). Furthermore, carvacrol was shown to be effective regardless of the maturity of the biofilm. The terpenoid phenols tested were able to inhibit biofilms of several strains of Candida, including C. albicans, C. glabrata, and C. parapsilosis. In addition to their antimycotic, antibacterial, insecticidal, and bioherbicidal properties, essential oils are also well known for their antioxidant characteristics and are used to inhibit lipid peroxidation in preventing food spoilage or as chemoprotective agen...

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