Antifungal and antioxidant activities of the phytomedicine pipsissewa, Chimaphila umbellata

Galván, Imelda J.; Mir-Rashed, Nadereh; Jessulat, Matthew; Atanya, Monica; Golshani, Ashkan; Durst, Tony; Petit, Philippe; Amiguet, Virginie Treyvaud; Boekhout, Teun; Summerbell, Richard C.; Cruz, Isabel B.; Arnason, John T.; Smith, Myron L.

doi:10.1016/j.phytochem.2007.09.007

Cited by 44 publications

(30 citation statements)

References 24 publications

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“…YPD agar plates without (control), and with a subinhibitory concentration of eugenol (0.18 mg/ml, experimental), were inoculated by hand-pinning sets of 384 mutant strains per plate using a floating pin replicator as previously described [18]. After 1–2 days incubation at 30°C, digital images of the plates were captured and analyzed using Growth Detector software [19].…”

Section: Methodsmentioning

confidence: 99%

The Antifungal Eugenol Perturbs Dual Aromatic and Branched-Chain Amino Acid Permeases in the Cytoplasmic Membrane of Yeast

et al. 2013

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Eugenol is an aromatic component of clove oil that has therapeutic potential as an antifungal drug, although its mode of action and precise cellular target(s) remain ambiguous. To address this knowledge gap, a chemical-genetic profile analysis of eugenol was done using ∼4700 haploid Saccharomyces cerevisiae gene deletion mutants to reveal 21 deletion mutants with the greatest degree of susceptibility. Cellular roles of deleted genes in the most susceptible mutants indicate that the main targets for eugenol include pathways involved in biosynthesis and transport of aromatic and branched-chain amino acids. Follow-up analyses showed inhibitory effects of eugenol on amino acid permeases in the yeast cytoplasmic membrane. Furthermore, phenotypic suppression analysis revealed that eugenol interferes with two permeases, Tat1p and Gap1p, which are both involved in dual transport of aromatic and branched-chain amino acids through the yeast cytoplasmic membrane. Perturbation of cytoplasmic permeases represents a novel antifungal target and may explain previous observations that exposure to eugenol results in leakage of cell contents. Eugenol exposure may also contribute to amino acid starvation and thus holds promise as an anticancer therapeutic drug. Finally, this study provides further evidence of the usefulness of the yeast Gene Deletion Array approach in uncovering the mode of action of natural health products.

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Section: Methodsmentioning

confidence: 99%

The Antifungal Eugenol Perturbs Dual Aromatic and Branched-Chain Amino Acid Permeases in the Cytoplasmic Membrane of Yeast

et al. 2013

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“…However, the inactivity of a second functionally overlapping pathway, in this case using a chemical treatment, can cause a "double hit" effect and result in a phenotypic consequence that can be scored as a reduction in the rate of growth, or a sick/sensitive phenotype [4,9]. Similarly, such chemical-genetic profile analyses can be used to study cellular target sites of various bioactive compounds [9], pharmaceuticals [10] and herbal extracts [11] whose mechanisms of action are unknown.…”

Section: Introductionmentioning

confidence: 99%

Chemical-genetic profile analysis of five inhibitory compounds in yeast

et al. 2010

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BackgroundChemical-genetic profiling of inhibitory compounds can lead to identification of their modes of action. These profiles can help elucidate the complex interactions between small bioactive compounds and the cell machinery, and explain putative gene function(s).ResultsColony size reduction was used to investigate the chemical-genetic profile of cycloheximide, 3-amino-1,2,4-triazole, paromomycin, streptomycin and neomycin in the yeast Saccharomyces cerevisiae. These compounds target the process of protein biosynthesis. More than 70,000 strains were analyzed from the array of gene deletion mutant yeast strains. As expected, the overall profiles of the tested compounds were similar, with deletions for genes involved in protein biosynthesis being the major category followed by metabolism. This implies that novel genes involved in protein biosynthesis could be identified from these profiles. Further investigations were carried out to assess the activity of three profiled genes in the process of protein biosynthesis using relative fitness of double mutants and other genetic assays.ConclusionChemical-genetic profiles provide insight into the molecular mechanism(s) of the examined compounds by elucidating their potential primary and secondary cellular target sites. Our follow-up investigations into the activity of three profiled genes in the process of protein biosynthesis provided further evidence concerning the usefulness of chemical-genetic analyses for annotating gene functions. We termed these genes TAE2, TAE3 and TAE4 for translation associated elements 2-4.

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“…Chimaphilin was purified from dried Chimaphila umbellata (L.) W. Bart (Pyrolaceae) as described by Galván et al (Galván et al, 2007). Nordihydroguaiaretic acid (NDGA) and ascorbic acid were obtained from Calbiochem (Darmstadt, Germany).…”

Section: General Methodsmentioning

confidence: 99%

“…Previously, a GDA analysis revealed that mutations in genes involved in mRNA transcription and cell wall functions were prevalent among those strains most sensitive to chimaphilin (Galván et al, 2007). We used a β-galactosidase reporter gene in yeast to monitor transcriptional activity by measuring o-nitrophenol production from o-nitrophenyl-β-D-galactoside (ONPG).…”

Section: Reporter Gene Expression Assay To Test Effects On Fungal Tramentioning

confidence: 99%

Secondary Assays for Testing the Mode of Action of Natural Products with Bioactivity Against Fungi

Smith

Cruz

Golshani

et al. 2008

Pharmaceutical Biology

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Identification of novel antifungals is needed, and plantderived compounds offer important leads in this respect. This article initiates a compendium of secondary assays for testing hypotheses on mode of action of plant-derived compounds. Three assays were developed to evaluate compounds that are hypothesized to effect cell wall function, transcription, and oxidative stress. A hypothesized perturbation on cell wall integrity by chimaphilin and Echinacea root extracts was supported using sonication and heat shock assays. Heat shock treatments reduced the number of viable cells recovered when yeast was grown in the presence of subinhibitory concentrations of chimaphilin. A reduction in cell numbers was also observed with both sonicationbased and heat shock-based assays when yeast was grown in the presence of Echinacea purpurea (L.) Moench (Asteraceae) extracts. The hypothesis that chimaphilin impedes mRNA transcription processes was also supported by a β-galactosidase reporter gene assay. The antioxidant activity of nordihydroguaiaretic acid (NDGA) and ascorbic acid were assessed using a yeast strain that does not grow under hyperoxic conditions. At the concentrations assayed, NDGA did not remediate this sensitivity to hyperoxia, whereas ascorbic acid did. These and additional assays are further reviewed with an aim to collate and standardize secondary assays and streamline antifungal mode of action determinations.

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Antifungal and antioxidant activities of the phytomedicine pipsissewa, Chimaphila umbellata

Cited by 44 publications

References 24 publications

The Antifungal Eugenol Perturbs Dual Aromatic and Branched-Chain Amino Acid Permeases in the Cytoplasmic Membrane of Yeast

The Antifungal Eugenol Perturbs Dual Aromatic and Branched-Chain Amino Acid Permeases in the Cytoplasmic Membrane of Yeast

Chemical-genetic profile analysis of five inhibitory compounds in yeast

Secondary Assays for Testing the Mode of Action of Natural Products with Bioactivity Against Fungi

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