Identification of the Antifungal Metabolite Chaetoglobosin P From Discosia rubi Using a Cryptococcus neoformans Inhibition Assay: Insights Into Mode of Action and Biosynthesis

Perlatti, Bruno; Nichols, Connie B.; Li, Nan; Wiemann, Philipp; Harvey, Colin J. B.; Alspaugh, J. Andrew; Bills, Gerald F.

doi:10.3389/fmicb.2020.01766

Cited by 6 publications

(4 citation statements)

References 55 publications

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“…The antifungal activity produced by strains was tracked by HPLC microfractionation followed by liquid growth inhibition assay directly in the plates used for fractionation as described previously ( Perlatti, Nichols, Lan, et al, 2020 ). Briefly, the HPLC eluents from an Ace Equivalence C 18 150 × 4.6 mm, 5 μ m, 35°C, 10–100% A over 20 min, holding 100% for 4 min, 1.0 ml min −1 were collected with a fraction collector.…”

Section: Methodsmentioning

confidence: 99%

Anti-cryptococcal activity of preussolides A and B, phosphoethanolamine-substituted 24-membered macrolides, and leptosin C from coprophilous isolates of Preussia typharum

Perlatti

Xiang

et al. 2021

Journal of Industrial Microbiology and Biotechnology

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Cryptococcus neoformans is a serious human pathogen with limited options for treatment. We have interrogated extracts from fungal fermentations to find Cryptococcus-inhibiting natural products using assays for growth inhibition and differential thermosensitivity. Extracts from fermentations of four fungal strains from wild and domestic animal dung from Arkansas and West Virginia, USA were identified as Preussia typharum. The extracts exhibited two antifungal regions. Purification of one region yielded new 24-carbon macrolides incorporating both a phosphoethanolamine unit and a bridging tetrahydrofuran ring. The structures of these metabolites were established mainly by analysis of high-resolution mass spectrometry and 2D NMR data. Relative configurations were assigned using NOESY data, and the structure assignments were supported by NMR comparison with similar compounds. These new metabolites are designated preussolides A and B. The second active region was caused by the cytotoxin, leptosin C. Genome sequencing of the four strains revealed biosynthetic gene clusters consistent with those known to encode phosphoethanolamine-bearing polyketide macrolides and the biosynthesis of dimeric epipolythiodioxopiperazines. All three compounds showed moderate to potent and selective antifungal activity towards the pathogenic yeast C. neoformans.

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Section: Methodsmentioning

confidence: 99%

Anti-cryptococcal activity of preussolides A and B, phosphoethanolamine-substituted 24-membered macrolides, and leptosin C from coprophilous isolates of Preussia typharum

Perlatti

Xiang

et al. 2021

Journal of Industrial Microbiology and Biotechnology

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“…7) 48 . PydY and its homologues, namely ScpY 48 , PN3-20 49 , G73 50 , and MGG_15096 51 , have been found in the biosynthetic pathways of a few fungal polyketide-nonribosomal peptide hybrid molecules; however, their prevalence in fungal natural product pathways has not been investigated. The global genome analysis resulted in the detection of more than 300 BGCs with a pydY homologue (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Tang,

Matsuda

2024

Nat Commun

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Genomics-guided methodologies have revolutionized the discovery of natural products. However, a major challenge in the field of genome mining is determining how to selectively extract biosynthetic gene clusters (BGCs) for untapped natural products from numerous available genome sequences. In this study, we developed a fungal genome mining tool that extracts BGCs encoding enzymes that lack a detectable protein domain (i.e., domainless enzymes) and are not recognized as biosynthetic proteins by existing bioinformatic tools. We searched for BGCs encoding a homologue of Pyr4-family terpene cyclases, which are representative examples of apparently domainless enzymes, in approximately 2000 fungal genomes and discovered several BGCs with unique features. The subsequent characterization of selected BGCs led to the discovery of fungal onoceroid triterpenoids and unprecedented onoceroid synthases. Furthermore, in addition to the onoceroids, a previously unreported sesquiterpene hydroquinone, of which the biosynthesis involves a Pyr4-family terpene cyclase, was obtained. Our genome mining tool has broad applicability in fungal genome mining and can serve as a beneficial platform for accessing diverse, unexploited natural products.

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“…More specifically, the upregulated quelling candidates are predicted to encode 16 chitinases, 17 glucanases, and seven mannanases (Table 1, and Supplementary File 1) that were demonstrated in the biocontrol agent Trichoderma to be involved in inhibiting the growth of phytopathogens (Lopes et al, 2012;Geraldine et al, 2013;Vos et al, 2015). Of the ten differentially upregulated biosynthetic gene clusters, seven are predicted to produce antifungal compounds such as (-)-Mellein, Chaetoglobosin, and Oxaleimide (Chen et al, 2015;Perlatti et al, 2020;Reveglia et al, 2020), and putative cytotoxic compounds such as Sansalvamide, Communesin, Squalestatin S1, and Wortmanamide (see Table 2; Belofsky et al, 1999;Trost and Osipov, 2015;Bonsch et al, 2016;Hai and Tang, 2018). The compounds synthesized by the remaining three clusters are unknown but are assumed to act as antifungals as well.…”

Section: Gene Expression Of Ec4 When Co-cultured With the Pathogenmentioning

confidence: 99%

A biofertilizing fungal endophyte of cranberry plants suppresses the plant pathogen Diaporthe

Thimmappa,

Salhi,

Forget

et al. 2024

Front. Microbiol.

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Fungi colonizing plants are gaining attention because of their ability to promote plant growth and suppress pathogens. While most studies focus on endosymbionts from grasses and legumes, the large and diverse group of ericaceous plants has been much neglected. We recently described one of the very few fungal endophytes promoting the growth of the Ericaceae Vaccinium macrocarpon (American cranberry), notably the Codinaeella isolate EC4. Here, we show that EC4 also suppresses fungal pathogens, which makes it a promising endophyte for sustainable cranberry cultivation. By dual-culture assays on agar plates, we tested the potential growth suppression (or biocontrol) of EC4 on other microbes, notably 12 pathogenic fungi and one oomycete reported to infect not only cranberry but also blueberry, strawberry, tomato plants, rose bushes and olive trees. Under greenhouse conditions, EC4 protects cranberry plantlets infected with one of the most notorious cranberry-plant pathogens, Diaporthe vaccinii, known to cause upright dieback and berry rot. The nuclear genome sequence of EC4 revealed a large arsenal of genes potentially involved in biocontrol. About ∼60 distinct clusters of genes are homologs of secondary metabolite gene clusters, some of which were shown in other fungi to synthesize nonribosomal peptides and polyketides, but in most cases, the exact compounds these clusters may produce are unknown. The EC4 genome also encodes numerous homologs of hydrolytic enzymes known to degrade fungal cell walls. About half of the nearly 250 distinct glucanases and chitinases are likely involved in biocontrol because they are predicted to be secreted outside the cell. Transcriptome analysis shows that the expression of about a quarter of the predicted secondary-metabolite gene clusters and glucan and chitin-degrading genes of EC4 is stimulated when it is co-cultured with D. vaccinii. Some of the differentially expressed EC4 genes are alternatively spliced exclusively in the presence of the pathogen, altering the proteins’ domain content and subcellular localization signal, thus adding a second level of proteome adaptation in response to habitat competition. To our knowledge, this is the first report of Diaporthe-induced alternative splicing of biocontrol genes.

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Identification of the Antifungal Metabolite Chaetoglobosin P From Discosia rubi Using a Cryptococcus neoformans Inhibition Assay: Insights Into Mode of Action and Biosynthesis

Cited by 6 publications

References 55 publications

Anti-cryptococcal activity of preussolides A and B, phosphoethanolamine-substituted 24-membered macrolides, and leptosin C from coprophilous isolates of Preussia typharum

Anti-cryptococcal activity of preussolides A and B, phosphoethanolamine-substituted 24-membered macrolides, and leptosin C from coprophilous isolates of Preussia typharum

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

A biofertilizing fungal endophyte of cranberry plants suppresses the plant pathogen Diaporthe

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