title: α-Bisabolol inhibits Aspergillus fumigatus Af239 growth via affecting microsomal ∆24-sterol methyltransferase as a crucial enzyme in ergosterol biosynthesis pathway.
abstract: Finding new compounds with antifungal properties is an important task due to the side effects of common antifungal drugs and emerging antifungal resistance in fungal strains. ∆24-sterol methyltransferase (24-SMT) is a crucial enzyme that plays important roles in fungal ergosterol biosynthesis pathway and is not found in humans. In the present study, the effects of α-bisabolol on Aspergillus fumigatus Af239 growth and ergosterol synthesis on the base of 24-SMT enzyme activity were studied; in addition, the expression of erg6, the gene encoded 24-SMT, was considered. To our knowledge, this is the first report demonstrating that α-bisabolol inhibits A. fumigatus growth specifically via suppressing fungal 24-SMT. Since this enzyme is a specific fungal enzyme not reported to exist in mammalian cells, α-bisabolol may serve as a lead compound in the development of new antifungal drugs. Fungi were cultured in presence of serial concentrations of α-bisabolol (0.281-9 mM) for 3 days at 35 °C. Mycelia dry weight was determined as an index of fungal growth and ergosterol content was assessed. Microsomal 24-SMT activity was assayed in presence of α-bisabolol as an inhibitor, lanosterol as a substrate and [methyl-H3] AdoMet (S-Adenosyl methionin). In addition, the expression of erg 6 gene (24-SMT encoding gene) was determined after treatments with various concentrations of α-bisabolol. Our results demonstrated that α-bisabolol strongly inhibited A. fumigatus growth (35.53-77.17%) and ergosterol synthesis (26.31-73.77%) dose-dependently and suppressed the expression of erg 6 gene by 76.14% at the highest concentration of 9 mM. α-bisabolol inhibited the activity of 24-SMT by 99% at the concentration of 5 mM. Taken together, these results provides an evidence for the first time that α-bisabolol inhibits A. fumigatus Af239 growth via affecting microsomal ∆24-sterol methyltransferase as a crucial enzyme in ergosterol biosynthetic pathway.
authors.affiliation: Department of Mycology, Pasteur Institute of Iran, 13164, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Jahanshiri
authors.affiliation: Department of Mycology, Faculty of Medical Sciences, Tarbiat Modares University, 14115-331, Tehran, Iran.
authors.forename: Masoomeh
authors.initials: M
authors.lastname: Shams-Ghahfarokhi
authors.affiliation: Department of Mycology, Pasteur Institute of Iran, 13164, Tehran, Iran.
authors.forename: Farnoush
authors.initials: F
authors.lastname: Asghari-Paskiabi
authors.affiliation: Department of Biochemistry, Pasteur Institute of Iran, 13164, Tehran, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Saghiri
authors.affiliation: Department of Mycology, Pasteur Institute of Iran, 13164, Tehran, Iran. mrab442@yahoo.com.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Razzaghi-Abyaneh
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D053898:Biosynthetic Pathways / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004875:Ergosterol / Q000096:biosynthesis; D005656:Fungal Proteins / Q000037:antagonists & inhibitors; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D000081222:Monocyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D000081222:Monocyclic Sesquiterpenes; D012717:Sesquiterpenes; C004497:bisabolol; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase; D004875:Ergosterol
keywords: Antifungal activity; Aspergillus fumigatus; Ergosterol biosynthesis; α-Bisabolol; ∆24-Sterol methyltransferase