Mechanism of antifungal activity of terpenoid phenols resembles calcium stress and inhibition of the TOR pathway

Anjana Rao, Yongqiang Zhang, Sabina Muend, Rajini Rao

Research output: Contribution to journalArticle

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 Ca2+ transients. Using a panel of related compounds, we observed dose-dependent Ca2+ bursts that correlated with antifungal efficacy. Changes in pH were long lasting and followed the Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)5062-5069
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume54
Issue number12
DOIs
StatePublished - Dec 1 2010

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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