Attenuation of phytofungal pathogenicity of Ascomycota by autophagy modulators

Jongchan Woo, Seungmee Jung, Seongbeom Kim, Yurong Li, Hyunjung Chung, Tatiana V. Roubtsova, Honghong Zhang, Celine Caseys, Dan Kliebenstein, Kyung-Nam Kim, Richard M. Bostock, Yong-Hwan Lee, Martin B. Dickman, Doil Choi (), Eunsook Park () and Savithramma P. Dinesh-Kumar ()
Additional contact information
Jongchan Woo: University of California
Seungmee Jung: University of Wyoming
Seongbeom Kim: Seoul National University
Yurong Li: Texas A & M University
Hyunjung Chung: Seoul National University
Tatiana V. Roubtsova: University of California
Honghong Zhang: Texas A & M University
Celine Caseys: University of California
Dan Kliebenstein: University of California
Kyung-Nam Kim: Sejong University
Richard M. Bostock: University of California
Yong-Hwan Lee: Seoul National University
Martin B. Dickman: Texas A & M University
Doil Choi: Seoul National University
Eunsook Park: University of Wyoming
Savithramma P. Dinesh-Kumar: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Autophagy in eukaryotes functions to maintain homeostasis by degradation and recycling of long-lived and unwanted cellular materials. Autophagy plays important roles in pathogenicity of various fungal pathogens, suggesting that autophagy is a novel target for development of antifungal compounds. Here, we describe bioluminescence resonance energy transfer (BRET)-based high-throughput screening (HTS) strategy to identify compounds that inhibit fungal ATG4 cysteine protease-mediated cleavage of ATG8 that is critical for autophagosome formation. We identified ebselen (EB) and its analogs ebselen oxide (EO) and 2-(4-methylphenyl)−1,2-benzisothiazol-3(2H)-one (PT) as inhibitors of fungal pathogens Botrytis cinerea and Magnaporthe oryzae ATG4-mediated ATG8 processing. The EB and its analogs inhibit spore germination, hyphal development, and appressorium formation in Ascomycota pathogens, B. cinerea, M. oryzae, Sclerotinia sclerotiorum and Monilinia fructicola. Treatment with EB and its analogs significantly reduced fungal pathogenicity. Our findings provide molecular insights to develop the next generation of antifungal compounds by targeting autophagy in important fungal pathogens.

Date: 2024
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DOI: 10.1038/s41467-024-45839-2

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