Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids.

Autor:	Edouarzin E; Department of Chemistry, 1212 Mid Campus Drive North, Kansas State University, Manhattan, KS 66506 USA., Horn C; Division of Biology, 1717 Claflin Road, Kansas State University, Manhattan, KS 66506 USA., Paudyal A; Division of Biology, 1717 Claflin Road, Kansas State University, Manhattan, KS 66506 USA., Zhang C; Department of Chemistry, 1212 Mid Campus Drive North, Kansas State University, Manhattan, KS 66506 USA., Lu J; Department of Chemistry, 1212 Mid Campus Drive North, Kansas State University, Manhattan, KS 66506 USA., Tong Z; Department of Chemistry, 1212 Mid Campus Drive North, Kansas State University, Manhattan, KS 66506 USA., Giaever G; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC Canada V6T 1Z3., Nislow C; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC Canada V6T 1Z3., Veerapandian R; Division of Biology, 1717 Claflin Road, Kansas State University, Manhattan, KS 66506 USA., Hua DH; Department of Chemistry, 1212 Mid Campus Drive North, Kansas State University, Manhattan, KS 66506 USA., Vediyappan G; Division of Biology, 1717 Claflin Road, Kansas State University, Manhattan, KS 66506 USA.
Jazyk:	angličtina
Zdroj:	Microbial cell (Graz, Austria) [Microb Cell] 2020 Mar 12; Vol. 7 (6), pp. 146-159. Date of Electronic Publication: 2020 Mar 12.
DOI:	10.15698/mic2020.06.719
Abstrakt:	Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1 R ,2 R ,4a S ,8a S )-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against C. albicans . (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 - 64 µg/ml, causing 100% death of various fungi), acts not only against C. albicans in a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Saksenaea and fluconazole resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest that drimenol is a broad-spectrum antifungal agent. At a high concentration (100 μg/ml) drimenol caused rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans -mediated death, indicating drimenol is tolerable and bioactive in metazoans. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutant spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and orf19.759, orf19.1672, and orf19.4382 were revealed to be involved in drimenol's mechanism of action. The three orfs identified in this study are novel and appear to be linked with Crk1 function. Further, computational modeling results suggest possible modifications of the structure of drimenol, including the A ring, for improving the antifungal activity. Competing Interests: Conflict of interest: A US patent (US 8,980,951 B2) on synthetic drimenol was approved in 2015 to Kansas State University Research Foundation (KSURF) with authors GV and DHH. (Copyright: © 2020 Edouarzin et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu