Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids

Authors:

Edruce Edouarzin1, Connor Horn2, Anuja Paudyal2, Cunli Zhang1, Jianyu Lu1, Zongbo Tong1, Guri Giaever3, Corey Nislow3, Raja Veerapandian2, Duy H. Hua1 and Govindsamy Vediyappan2

doi: 10.15698/mic2020.06.719
Volume 7, pp. 146 to 159, published 12/03/2020.

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Affiliations:

1 Department of Chemistry, 1212 Mid Campus Drive North, Kansas State University, Manhattan, KS 66506 USA.

2 Division of Biology, 1717 Claflin Road, Kansas State University, Manhattan, KS 66506 USA.

3 Faculty of Pharmaceutical Sciences, University of British Columbia,Vancouver, BC Canada V6T 1Z3.

Keywords: 

drimenol, synthesis, Candida albicans, Candida auris, Saccharomyces cerevisiae, fungicidal antifungal, novel mechanism of action, Crk1 kinase associated

Corresponding Author(s):

Govindsamy Vediyappan, 1717 Claflin Road, Division of Biology, Kansas State University, Manhattan KS 66506 Tel. 785 532 6662, Fax. 785 532 6653; gvediyap@ksu.edu

Conflict of interest statement:

A US patent (US 8,980,951 B2) on synthetic drimenol was approved in 2015 to Kansas State University Re-search Foundation (KSURF) with authors GV and DHH.

Please cite this article as:

Edruce Edouarzin, Connor Horn, Anuja Paudyal, Cunli Zhang, Jianyu Lu, Zongbo Tong, Guri Giaever, Corey Nislow, Raja Veera-pandian, Duy H. Hua and Govindsamy Vediyappan (2020). Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids. Microbial Cell 7(6): 146-159. doi: 10.15698/mic2020.06.719

© 2020 Edouarzin et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-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.