{"title":"Host–Pathogen Interaction Activated Biosynthesis of Natural Products","authors":"Yukiko Ujie, , , Shun Saito, , , Chisato Iwata, , , Ruri Kuwahara, , , Shinji Kishimoto, , , Kenji Watanabe, , , Yoshikuni Goto, , , Kenji Ogawa, , , Yasumasa Hara, , , Yoko Kusuya, , , Hiroki Takahashi, , , Takashi Yaguchi, , , Masami Ishibashi, , and , Midori A. Arai*, ","doi":"10.1021/acs.jnatprod.5c00776","DOIUrl":null,"url":null,"abstract":"<p >The way immune cells attack pathogenic microorganisms might trigger pathogens to produce compounds that promote their survival. Based on this idea, we constructed a coculture system of pathogenic fungi and immune cells and isolated fumigatinolactone (<b>1</b>) as a new natural product by coculture of <i>Aspergillus fumigatus</i> IFM 60237 with RAW264 mouse macrophage-like cells. Fumigatinolactone (<b>1</b>) was produced via a nonenzymatic coupling reaction between fumigatin (<b>4</b>) and a new type of intermediate fumarylazlactone (<b>5</b>). An investigation of the interaction mechanism between the fungi and cells revealed that the survival interaction between pathogen and immune cells played key roles. Surprisingly, fungi showed a response to nitric oxide (NO), which was produced by macrophages, resulting in the production of <b>4</b>. In addition, an iron starvation condition triggered the production of <b>5</b>. Finally, <b>1</b> was obtained by these two mechanisms. Furthermore, compounds <b>1</b>–<b>4</b>, particularly <b>4</b>, showed inhibition of NO production from RAW264, which might be a defense action for macrophage by fungi. This is the first example of elucidation of interaction mechanisms between pathogen and immune cells for activation of silent genes to produce a new compound. These findings suggest that host–pathogen survival interaction may increase the production of secondary metabolites from fungi.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"88 9","pages":"2204–2215"},"PeriodicalIF":3.6000,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Natural Products ","FirstCategoryId":"99","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jnatprod.5c00776","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
The way immune cells attack pathogenic microorganisms might trigger pathogens to produce compounds that promote their survival. Based on this idea, we constructed a coculture system of pathogenic fungi and immune cells and isolated fumigatinolactone (1) as a new natural product by coculture of Aspergillus fumigatus IFM 60237 with RAW264 mouse macrophage-like cells. Fumigatinolactone (1) was produced via a nonenzymatic coupling reaction between fumigatin (4) and a new type of intermediate fumarylazlactone (5). An investigation of the interaction mechanism between the fungi and cells revealed that the survival interaction between pathogen and immune cells played key roles. Surprisingly, fungi showed a response to nitric oxide (NO), which was produced by macrophages, resulting in the production of 4. In addition, an iron starvation condition triggered the production of 5. Finally, 1 was obtained by these two mechanisms. Furthermore, compounds 1–4, particularly 4, showed inhibition of NO production from RAW264, which might be a defense action for macrophage by fungi. This is the first example of elucidation of interaction mechanisms between pathogen and immune cells for activation of silent genes to produce a new compound. These findings suggest that host–pathogen survival interaction may increase the production of secondary metabolites from fungi.
期刊介绍：
The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained.
Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.
When new compounds are reported, manuscripts describing their biological activity are much preferred.
Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.
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