Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad‐spectrum antifungal activity

Abstract

As phospholipids of cell membranes, phosphatidylethanolamine (PE) and phosphatidylserine (PS) play crucial roles in glycerophospholipid metabolism. Broadly, some phospholipid biosynthesis enzymes serve as potential fungicide targets. Therefore, revealing the functions and mechanism of PE biosynthesis in plant pathogens would provide potential targets for crop disease control.We performed analyses including phenotypic characterizations, lipidomics, enzyme activity, site-directed mutagenesis, and chemical inhibition assays to study the function of PS decarboxylase-encoding gene MoPSD2 in rice blast fungus Magnaporthe oryzae.The Mopsd2 mutant was defective in development, lipid metabolism, and plant infection. The PS level increased while PE decreased in Mopsd2, consistent with the enzyme activity. Furthermore, chemical doxorubicin inhibited the enzyme activity of MoPsd2 and showed antifungal activity against 10 phytopathogenic fungi including M. oryzae and reduced disease severity of two crop diseases in the field. Three predicted doxorubicin-interacting residues are important for MoPsd2 functions.Our study demonstrates that MoPsd2 is involved in de novo PE biosynthesis and contributes to the development and plant infection of M. oryzae and that doxorubicin shows broad-spectrum antifungal activity as a fungicide candidate. The study also implicates that bacterium Streptomyces peucetius, which biosynthesizes doxorubicin, could be potentially used as an eco-friendly biocontrol agent.

Rational modification of melatonin for broad‐spectrum antifungal agents discovery

“…Due to the highly conserved protein structures of fungal Mps1 homologs as the target, Mt‐23 significantly inhibited mycelial growth of seven fungal pathogens and effectively alleviated the severity of various diseases, including rice blast, Fusarium head blight of wheat, gray mold of tomato, leaf blight of corn, and sclerotinia stem rot of rape. These are consistent with the results of most drugs designed to interact with conserved targets, such as doxorubicin targeting the conserved phosphatidylserine decarboxylase of fungal pathogens resulting in more effective control of fungi including M. oryzae and B. cinerea 62 …”

“…These are consistent with the results of most drugs designed to interact with conserved targets, such as doxorubicin targeting the conserved phosphatidylserine decarboxylase of fungal pathogens resulting in more effective control of fungi including M. oryzae and B. cinerea. 62 Currently, natural antifungal agents are widely used in disease control. Monoterpene phenol thymol extracted from Thymus mongolicus effectively inhibits Fusarium oxysporum infection in potato; alkaloids effectively inhibit B. cinerea infection in grapes and improve the storage quality of fruits.…”

Microscopic and Transcriptomic Analyses to Elucidate Antifungal Mechanisms of Bacillus velezensis TCS001 Lipopeptides against Botrytis cinerea

“…3,40 Similarly, the Magnaporthe oryzae Mopsd2 mutant presented defective development, lipid metabolism, and plant infection, as demonstrated by Zhou et al 41 The study also implicated doxorubicin, an antibiotic produced by Streptomyces peucetius, is empowered with broad spectrum antifungal activity via acting on PSD. 41 In this study, we generated Bcpsd mutants and confirmed that Bcpsd is required for mycelial growth and host infection in B. cinerea. Hence, it is proven that TCS001 CLE affects the growth of B. cinerea by suppressing the expression of Bcpsd.…”

“…FgPsd2 was demonstrated to be indispensable for the development and virulence of Fusarium graminearum . Deletion of fgPsd 2 resulted in decreased vegetative growth and conidiation, along with defects in virulence and DON production. , Similarly, the Magnaporthe oryzae Mopsd 2 mutant presented defective development, lipid metabolism, and plant infection, as demonstrated by Zhou et al The study also implicated doxorubicin, an antibiotic produced by Streptomyces peucetius , is empowered with broad spectrum antifungal activity via acting on PSD . In this study, we generated Bcpsd mutants and confirmed that Bcpsd is required for mycelial growth and host infection in B. cinerea .…”