Abstract
Repetitive uses of antifungals result in a worldwide crisis of drug resistance; therefore, natural fungicides with minimal side-effects are currently sought after. This study aimed to investigate antifungal property of 19, 20-epoxycytochalasin Q (ECQ), derived from medicinal mushroom Xylaria sp. BCC 1067 of tropical forests. In a model yeast Saccharomyces cerevisiae, ECQ is more toxic in the erg6∆ strain, which has previously been shown to allow higher uptake of many hydrophilic toxins. We selected one pathway to study the effects of ECQ at very high levels on transcription: the ergosterol biosynthesis pathway, which is unlikely to be the primary target of ECQ. Ergosterol serves many functions that cholesterol does in human cells. ECQ’s transcriptional effects were correlated with altered sterol and triacylglycerol levels. In the ECQ-treated Δerg6 strain, which presumably takes up far more ECQ than the wild-type strain, there was cell rupture. Increased actin aggregation and lipid droplets assembly were also found in the erg6∆ mutant. Thereby, ECQ is suggested to sensitize yeast cells lacking ERG6 through actin-targeting and consequently but not primarily led to disruption of lipid homeostasis. Investigation of cytochalasins may provide valuable insight with potential biopharmaceutical applications in treatments of fungal infection, cancer or metabolic disorder.
Highlights
Display lower toxicity[4,5]
To examine the antifungal action of epoxycytochalasin Q (ECQ), the susceptibility of mutant yeast strains with a deleted gene of the enzyme in the ergosterol biosynthetic pathway was first investigated since many of them are served as antifungal drug targets
Only the Δerg[6] strain had increased sensitivity to the Xylaria extract tested when compared to the wild-type S. cerevisiae strain, with exhibited M IC50, MIC80 and MFC values of 375 μg/ ml, 900 μg/ml and 2,000 μg/ml, respectively (Fig. 1c,d)
Summary
Display lower toxicity[4,5]. Azoles are commonly used in clinical practice despite their fungistatic effect which eventually leads to the development of drug resistance. Key step is the rate-limiting conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonic acid catalyzed by HMG-CoA reductase, encoded by the HMG1 and HMG28. These two isoenzymes display different modes of feedback control and r egulation[8]. Disruption of ERG genes in the late step of the ergosterol biosynthesis pathway results in lower activity of Pdr5p drug efflux transporter and susceptibility to s tresses[14]. Novel antifungals with effective fungicidal activity and specificity for fungal targets are important to fight against drug-resistant fungi. An alteration in sterol biosynthesis following ECQ treatment was investigated using S. cerevisiae wild-type and the Δerg[6] strains, which the latter lacks a key antifungal target enzyme of ergosterol biosynthesis, as a model for study
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