α-Bisabolol inhibits Aspergillus fumigatus Af239 growth via affecting microsomal ∆24-sterol methyltransferase as a crucial enzyme in ergosterol biosynthesis pathway
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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.
KeywordsAspergillus fumigatus α-Bisabolol ∆24-Sterol methyltransferase Ergosterol biosynthesis Antifungal activity
This work was financially supported by the Pasteur Institute of Iran (Project No. 647).
- Borba-Santos LP, Visbal G, Braga TG, Rodrigues AM, De Camargo ZP, Bezerra LLL-BL, Ishida K, De Souza W, Rozental S (2016) ∆24-sterol methyltransferase plays an important role in the growth and development of Sporothrix schenckii and Sporothrix brasiliensis. Front Microbiol 7:311. doi: 10.3389/00311 CrossRefGoogle Scholar
- Jensen-Pergakes KL, Kennedy MA, Lees ND, Barbuch R, Koegel C, Bard M (1998) Sequencing, disruption, and characterization of the Candida albicans sterol methyltransferase (ERG6) gene: drug susceptibility studies in erg6 mutants. Antimicrob Agents Chemother 42:1160–1167Google Scholar
- Moore TJ, Gaylor LJ (1969) Isolation and purification of an S-adenosylmethionine: ∆24-sterol methyltransferase from yeast. J Biol Chem 244(23):6334–6340Google Scholar
- Nes WD, McCourt BS, Zhou W-X, Ma J, Marshall JA, Peek L-A, Brennan M (1998) Overexpression, purification, and stereochemical studies of the recombinant (S)-adenosyl-l-methionine: ∆24 (25)-to ∆24 (28)-sterol methyltransferase enzyme from Saccharomyces cerevisiae. Arch Biochem Biophys 353(2):297–311CrossRefGoogle Scholar
- Pereira M, Song Z, Santos-Silva LK, Richards MH, Nguyen TTM, Liu J, de Almeida Soares CM, da Silva Cruz AH, Ganapathy K, Nes WD (2010) Cloning, mechanistic and functional analysis of a fungal sterol C24-methyltransferase implicated in brassicasterol biosynthesis. BBA-Mol Cell Biol Lipids 1801(10):1163–1174CrossRefGoogle Scholar
- Romagnoli C, Baldisserotto A, Malisardi G, Vicentini CB, Mares D, Andreotti E, Vertuani S, Manfredini S (2015) A multi-target approach toward the development of novel candidates for antidermatophytic activity: ultrastructural evidence on α-bisabolol-treated Microsporum gypseum. Molecules 20(7):11765–11776CrossRefGoogle Scholar
- Soape MP (2007) Protein chemistry, peptide mapping, and preliminary structural characterization of saccharomyces cerevisiae sterol ∆24-sterol methyltransferase expressed in Escherichia coli. Ms.c Thesis, Texas Tech UniversityGoogle Scholar
- Tolouee M, Alinezhad S, Saberi R, Eslamifar A, Zad SJ, Jaimand K, Taeb J, Rezaee M-B, Kawachi M, Shams-Ghahfarokhi M (2010) Effect of Matricaria chamomilla L. flower essential oil on the growth and ultrastructure of Aspergillus niger van Tieghem. Int J Food Microbiol 139(3):127–133CrossRefGoogle Scholar