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-1carbaldehyde (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.
Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida and Cryptococcus. In fact, the drug-resistant Can. krusei and the emerging pan-antifungal resistant Can. auris pose a serious threat to human health as the existing limited antifungals are futile. To further complicate therapy, fungi produce capsules and spores that are resistant to most antifungal drugs/host defenses. Novel antifungal drugs are urgently needed to fill unmet medical needs. From screening a collection of medicinal plant sources for antifungal activity, we have identified an active fraction from the rhizome of Cyperus rotundus, the nut grass plant. The fraction contained α-Cyperone, an essential oil that showed fungicidal activity against different species of Candida. Interestingly, the minimal inhibitory concentration of α-Cyperone was reduced 8-fold when combined with a clinical antifungal drug, fluconazole, indicating its antifungal synergistic potential and could be useful for combination therapy. Furthermore, α-Cyperone affected the synthesis of the capsule in Cryp. neoformans, a causative agent of fungal meningitis in humans. Further work on mechanistic understanding of α-Cyperone against fungal virulence could help develop a novel antifungal agent for drug-resistant fungal pathogens.
25Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized 26 from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, 27 (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-28 carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor 29 of the three, (at concentrations of 8 -64 g/ml, causing 100% death of fungi), acts not only against 30 C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, 31 Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. 32 albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol 33 is a broad-spectrum antifungal agent. At high concentration (100 μg/ml), drimenol caused a 34 rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol 35 rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive 36 in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential 37 homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections 38 revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot 39 assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets 40 orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. 41 Further, computational modeling results suggest possible modification of the structure of drimenol 42 including the A ring for improving antifungal activity. 43 44 45 46 47 48 Life-threatening fungal infections are an important cause of morbidity and mortality, 49 particularly for patients with immune deficiency and those who are undergoing chemotherapeutic 50 treatments. Some of the leading invasive fungal pathogens include Candida sp., Aspergillus sp. 51 and Cryptococcus sp. Currently, the antifungal therapeutic options are limited, especially when 52 compared to available antibacterial agents (1-4). Among the five classes of antifungals, azoles, 53 echiocandins, polyenes, allylamines, and pyrimidine derivatives, only three are used clinically; 54 azoles, echiocandins, and polyenes. Azole drugs, such as fluconazole (FLU), inhibit ergosterol 55 synthesis through inhibition of lanosterol 14--demethylase, impairing formation of the fungal 56 cell wall. Echocandins, such as caspofungin (CAS), block 1,3--glucan synthase and lead to 57 depletion of glucan in fungal cell wall. Polyenes, including amphotericin B (AMB), bind to 58 ergosterol in fungal cell membrane and change the cell membrane transition temperature, resulting 59 in leakage of ions and small organic molecules, and eventual cell death. Allylamines, such as 60 amorolfin, affect ergosterol synthesis by inhibition of squalene epoxidase. Pyrimidines, such as 61 flucytosine (or 5-fluorocytosine), block nucleic acid synthesis,...
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