Fungal-derived methyldeoxaphomins target Plasmodium falciparum segregation through the inhibition of PfActin1 DOI Creative Commons
Tiantian Jiang,

Jin Woo Lee,

Jennifer E. Collins

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(8)

Published: Feb. 18, 2025

Herein we report the finding and structure determination of a natural product based on methyldeoxaphomin scaffold family from fungus Trichocladium asperum that shows promising antiplasmodial activity selectivity against host cells. In vitro evolution whole genome analysis in Plasmodium falciparum with most potent member, NPDG-F (EC 50 550 nM Dd2; 290 3D7), parasite resistance to methyldeoxaphomins is strongly associated mutations PfActin1 (PF3D7_1246200), critically essential ATPase needed for all stages development. Molecular docking study available crystal occupies same allosteric binding pocket as known actin inhibitor cytochalasin D. The direct target engagement site was supported by cross-resistance studies, isobologram other inhibitors, structure–activity relationships family. When added culture, induced morphological abnormalities merozoite cellularization during schizogony both blood liver stages. Our data provide chemical validation an attractive, pan-lifecycle inform strategies design more selective inhibitors.

Language: Английский

Microbial secondary metabolites: advancements to accelerate discovery towards application DOI
Jaime Lorenzo N. Dinglasan, Hiroshi Otani, Drew T. Doering

et al.

Nature Reviews Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

Citations

4
Microbial chassis engineering drives heterologous production of complex secondary metabolites DOI
Jiaqi Liu, Xue Wang,

Guangzhi Dai

et al.

Biotechnology Advances, Journal Year: 2022, Volume and Issue: 59, P. 107966 - 107966

Published: April 26, 2022

Language: Английский

Citations

51
Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining DOI
Chen‐Yu Chiang, M. Ohashi, Yi Tang

et al.

Natural Product Reports, Journal Year: 2022, Volume and Issue: 40(1), P. 89 - 127

Published: Sept. 20, 2022

Covering: 2010 to 2022Heterologous expression of natural product biosynthetic gene clusters (BGCs) has become a widely used tool for genome mining cryptic pathways, bottom-up investigation enzymes, and engineered biosynthesis new variants. In the field fungal products, heterologous complete pathway was first demonstrated in tenellin

Language: Английский

Citations

46
Heterologous protein production in filamentous fungi DOI Creative Commons

Dujuan Liu,

Sandra Garrigues, Ronald P. de Vries

et al.

Applied Microbiology and Biotechnology, Journal Year: 2023, Volume and Issue: 107(16), P. 5019 - 5033

Published: July 5, 2023

Abstract Filamentous fungi are able to produce a wide range of valuable proteins and enzymes for many industrial applications. Recent advances in fungal genomics experimental technologies rapidly changing the approaches development use filamentous as hosts production both homologous heterologous proteins. In this review, we highlight benefits challenges using We review various techniques commonly employed improve protein fungi, such strong inducible promoters, codon optimization, more efficient signal peptides secretion, carrier proteins, engineering glycosylation sites, regulation unfolded response endoplasmic reticulum associated degradation, optimization intracellular transport process, unconventional construction protease-deficient strains. Key points • This updates knowledge on fungi. Several cell factories potential candidates discussed. Insights into improving gene expression given.

Language: Английский

Citations

35
The Potential Use of Fungal Co-Culture Strategy for Discovery of New Secondary Metabolites DOI Creative Commons
Shuang Xu, Mengshi Li, Zhe Hu

et al.

Microorganisms, Journal Year: 2023, Volume and Issue: 11(2), P. 464 - 464

Published: Feb. 12, 2023

Fungi are an important and prolific source of secondary metabolites (SMs) with diverse chemical structures a wide array biological properties. In the past two decades, however, number new fungal SMs by traditional monoculture method had been greatly decreasing. Fortunately, growing studies have shown that co-culture strategy is effective approach to awakening silent SM biosynthetic gene clusters (BGCs) in strains produce cryptic SMs. To enrich our knowledge this better exploit potential for drug discovery, review comprehensively summarizes all methods their derived as well bioactivities on basis extensive literature search data analysis. Future perspective study, its interaction mechanism, supplied.

Language: Английский

Citations

23
Detoxification of Ustiloxin A Through Oxidative Deamination and Decarboxylation by Endophytic Fungus Petriella setifera DOI Creative Commons
Peng Li, Gan Gu,

Xuwen Hou

et al.

Toxins, Journal Year: 2025, Volume and Issue: 17(2), P. 48 - 48

Published: Jan. 22, 2025

Ustiloxins are a group of cyclopeptide mycotoxins produced by rice false smut pathogen Villosiclava virens (anamorph: Ustilaginoidea virens) which seriously threaten the safety production and health humans livestock. Ustiloxin A, accounting for 60% total ustiloxins, is main toxic component. Biotransformation, process modifying functional groups compounds means regio- or stereo-specific reactions catalyzed enzymes organisms, has been considered as an efficient way to detoxify mycotoxins. In this study, endophytic fungus Petriella setifera Nitaf10 was found be able ustiloxin A through biotransformation. Two transformed products were obtained using cell-free extract (CFE) containing intracellular P. Nitaf10. They structurally characterized novel analogs named ustiloxins A1 (1) A2 (2) analysis 1D 2D NMR HRESIMS spectra well comparison with known ustiloxins. The cytotoxic activity much weaker than that A. biotransformation proceed via oxidative deamination decarboxylation possibly amine oxidase decarboxylase in CFE. An appropriate bioconversion achieved incubating CFE prepared 0.5 mol/L phosphate buffer (pH 7.0) 24 48 h. optimum initial pH values 7–9. Among eight metal ions (Co2+, Cu2+, Fe3+, Zn2+, Ba2+, Ca2+, Mg2+ Mn2+) tested at 5 mmol/L, Fe3+ Zn2+ totally inhibited conversion conclusion, detoxification strategy.

Language: Английский

Citations

1
Transcriptional Activation of Biosynthetic Gene Clusters in Filamentous Fungi DOI Creative Commons
László Mózsik, Riccardo Iacovelli,

Roel A. L. Bovenberg

et al.

Frontiers in Bioengineering and Biotechnology, Journal Year: 2022, Volume and Issue: 10

Published: July 15, 2022

Filamentous fungi are highly productive cell factories, many of which industrial producers enzymes, organic acids, and secondary metabolites. The increasing number sequenced fungal genomes revealed a vast unexplored biosynthetic potential in the form transcriptionally silent metabolite gene clusters (BGCs). Various strategies have been carried out to explore mine this untapped source bioactive molecules, with advent synthetic biology, novel applications, tools developed for filamentous fungi. Here we summarize approaches aiming expression endogenous or exogenous natural product BGCs, including transcription factors, assembly artificial units, cluster refactoring, shuttle vectors, platform strains.

Language: Английский

Citations

31
Strategies for Natural Product Discovery by Unlocking Cryptic Biosynthetic Gene Clusters in Fungi DOI Creative Commons

Ji Yun Hur,

Eunju Jeong, Young Chan Kim

et al.

Separations, Journal Year: 2023, Volume and Issue: 10(6), P. 333 - 333

Published: May 26, 2023

Recent advancements in genome sequencing and bioinformatic analysis of fungal genomes have revealed that fungi possess cryptic or silent biosynthetic gene clusters (BGCs). This discovery suggests our understanding the universe secondary metabolomes is limited. In this review, we summarize recent strategies for activating BGCs fungi, identify metabolites, highlight their biological activities. We also briefly discuss isolation purification methods these compounds. Our focus on genetics-dependent genetics-independent approaches fungi. Using discussed here, natural products hold significant potential as a source new drug candidates.

Language: Английский

Citations

17
Combinatorial biosynthesis for the engineering of novel fungal natural products DOI Creative Commons
Elizabeth Skellam, Sanjeevan Rajendran, Lei Li

et al.

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: April 18, 2024

Abstract Natural products are small molecules synthesized by fungi, bacteria and plants, which historically have had a profound effect on human health quality of life. These natural evolved over millions years resulting in specific biological functions that may be interest for pharmaceutical, agricultural, or nutraceutical use. Often need to structurally modified make them suitable applications. Combinatorial biosynthesis is method alter the composition enzymes needed synthesize product diversified molecules. In this review we discuss different approaches combinatorial via engineering fungal biosynthetic pathways. We highlight knowledge gained from these studies provide examples new-to-nature bioactive molecules, including using combinations non-fungal enzymes.

Language: Английский

Citations

7
Total Heterologous Biosynthesis of Fungal Natural Products in Aspergillus nidulans DOI
Yi‐Ming Chiang,

Tzu‐Shyang Lin,

Clay C. C. Wang

et al.

Journal of Natural Products, Journal Year: 2022, Volume and Issue: 85(10), P. 2484 - 2518

Published: Sept. 29, 2022

Fungal natural products comprise a wide range of bioactive compounds including important drugs and agrochemicals. Intriguingly, bioinformatic analyses fungal genomes have revealed that fungi the potential to produce significantly more than what been discovered so far. It has thus become widely accepted most biosynthesis pathways are silent or expressed at very low levels under laboratory cultivation conditions. To tap into this vast chemical reservoir, reconstitution entire biosynthetic in genetically tractable hosts (total heterologous biosynthesis) increasingly employed recent years. This review summarizes total accomplished before 2020 using Aspergillus nidulans as hosts. We here transformation, A. hosts, shuttle vectors for episomal expression, chromosomal integration expression. These tools, collectively, not only facilitate discovery cryptic but can also be used generate high-yield strains with clean metabolite backgrounds. In comparison synthesis, offers simplified strategy construct complex molecules holds commercial application.

Language: Английский

Citations

28