Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Plant-Derived Isoquinoline Alkaloids that Target Ergosterol Biosynthesis Discovered by Using a Novel Antifungal Screening Tool

Version 1 : Received: 18 October 2020 / Approved: 19 October 2020 / Online: 19 October 2020 (11:10:30 CEST)

How to cite: Wong-Deyrup, S.W.; Song, X.; Ng, T.; Liu, X.; Zeng, J.; Qing, Z.; Deyrup, S.T.; He, Z.; Zhang, H. Plant-Derived Isoquinoline Alkaloids that Target Ergosterol Biosynthesis Discovered by Using a Novel Antifungal Screening Tool. Preprints 2020, 2020100373 (doi: 10.20944/preprints202010.0373.v1). Wong-Deyrup, S.W.; Song, X.; Ng, T.; Liu, X.; Zeng, J.; Qing, Z.; Deyrup, S.T.; He, Z.; Zhang, H. Plant-Derived Isoquinoline Alkaloids that Target Ergosterol Biosynthesis Discovered by Using a Novel Antifungal Screening Tool. Preprints 2020, 2020100373 (doi: 10.20944/preprints202010.0373.v1).

Abstract

The ergosterol pathway is a prime antifungal target. The minimum inhibitory concentration (MIC) assay is a simple research tool that determines the lowest concentration at which a novel antimicrobial with limited scope to determine the mechanism of action for a drug. In this study, we show that by adding hydrogen peroxide, an oxidative stressor, or glutathione (GSH), an antioxidant, to modify a commonly performed MIC assay allowed us to screen selectively for new antifungal drugs that target ergosterol biosynthesis in fungi. A human pathogen, Microsporum gypseum, was used as a test organism. When exposed to ergosterol targeting drugs, the hydrogen peroxide treatment significantly decreased fungal survival by reducing ergosterol in the cell wall, whereas GSH increased survival of M. gypseum. Further, by performing a series of experiments with M. gypseum, it was determined that the oxidative stress from hydrogen peroxide causes cell death at different developmental stages. These findings allow us to describe a simple, high-throughput method for simultaneously screening new antifungal drugs for activity and effects on the ergosterol pathway. By using this tool, two isoquinoline alkaloids were discovered to be potent inhibitors of ergosterol biosynthesis by reducing the amount of ergosterol without affecting the expression of 1,3-β-glucan.

Subject Areas

Fungi; ergosterol pathway; dermatophytes; chelerythrine; sanguinarine

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