title: Thymol antifungal mode of action involves telomerase inhibition.
abstract: The antifungal mode of action of thymol was investigated by a chemical-genetic profile analysis. Growth of each of ~4700 haploid Saccharomyces cerevisiae gene deletion mutants was monitored on medium with a subinhibitory concentration (50 μg/ml) of thymol and compared to growth on non-thymol control medium. This analysis revealed that, of the 76 deletion mutants with the greatest degree of susceptibility to thymol, 29% had deletions in genes involved in telomere length maintenance. A telomere restriction fragment (TRF) length assay showed that yeast exposed to a subinhibitory concentration of thymol for 15 days had telomere size reductions of 13-20% compared to non-thymol controls. By accelerating telomere shortening, thymol may increase the rate of cell senescence and apoptosis. Furthermore, real-time RT-PCR analysis revealed approximately two-fold reductions in EST2 mRNA but no change in TLC1 RNA in thymol-treated S. cerevisiae relative to untreated cells. EST2 encodes the essential reverse transcriptase subunit of telomerase that uses TLC1 RNA as a template during addition of TG(1-3) repeats to maintain telomere ends. This study provides compelling evidence that a primary mode of thymol antifungal activity is through inhibition of transcription of EST2 and thus telomerase activity.
authors.affiliation: * Department of Agronomy and Plant Breeding, College of Agriculture, University of Tehran , Karaj , Iran.
authors.forename: Emad
authors.initials: E
authors.lastname: Darvishi
authors.forename: Mansoor
authors.initials: M
authors.lastname: Omidi
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Bushehri
authors.forename: Ashkan
authors.initials: A
authors.lastname: Golshani
authors.forename: Myron L
authors.initials: ML
authors.lastname: Smith
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D003470:Culture Media / Q000737:chemistry; D017353:Gene Deletion; D020869:Gene Expression Profiling; D008826:Microbial Sensitivity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013943:Thymol / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D003470:Culture Media; D029701:Saccharomyces cerevisiae Proteins; D013943:Thymol; C509185:EST2 protein, S cerevisiae; D019098:Telomerase