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BACKGROUND: Epicoccum sorghinum is a pathogenic fungus that causes leaf spot in a wide range of plants, including maize, and synthesizes the mycotoxin tenuazonic acid (TEA), which is carcinogenic. Despite the relevant economic and yield losses caused by E. sorghinum worldwide, methods for the control of this pathogen are lacking. RESULTS: In this work, the efficacy of Bacillus‐produced dipicolinic acid (DPA) for control of E. sorghinum was evaluated using in vitro and in vivo assays, and compared with the efficacy of three commercial fungicides, including carbendazim, prochloraz, and thiram. DPA inhibited E. sorghinum mycelial growth, and conidia germination, and produced important alterations in E. sorghinum hyphae. Interestingly, 10 mM DPA reduced TEA biosynthesis by 86.6%. Although DPA rapidly degraded on maize leaves, 10 mM DPA showed higher preventive (67.4% lesion length inhibition) and inhibitory (89.5% lesion length inhibition) efficacies for the control of E. sorghinum on maize leaves compared to the commercial fungicides. CONCLUSIONS: Collectively, this study presents the first method for the control of E. sorghinum on maize and demonstrates that DPA application is a suitable approach to inhibit E. sorghinum symptoms in plants and TEA biosynthesis. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Fungi are known to produce many chemically diversified metabolites, yet their ecological roles are not always fully understood. The blue cheese fungus Penicillium roqueforti thrives in different ecological niches and is known to produce a wide range of metabolites, including mycotoxins. Three P. roqueforti populations have been domesticated for cheese production and two populations thrive in other anthropized environments, i.e., food, lumber and silage. In this study, we looked for differences in targeted and untargeted metabolite production profiles between populations using HPLC-HR-Q-TOF and UHPLC-Q-TOF-HR-MS/MS. The non-cheese populations produced several fatty acids and different terpenoids, lacking in cheese strains. The Termignon cheese population displayed intermediate metabolite profiles between cheese and non-cheese populations, as previously shown for other traits. The non-Roquefort cheese population with the strongest domestication syndrome, produced the lowest quantities of measured metabolites, including mycophenolic acid (MPA), andrastin A and PR toxin. Its inability to produce MPA was due to a deletion in the mpaC gene, while a premature stop codon in ORF 11 of the PR toxin gene cluster explained PR toxin absence and the accumulation of its intermediates, i.e., eremofortins A and B. In the Roquefort population, we detected no PR toxin nor eremofortins A or B, but found no indel or frameshift mutation, suggesting downregulation. The hypotoxigenic trait of domesticated cheese populations can be hypothesized to be linked to the loss of this ability through trait degeneration and/or the selection of low toxin producers. It may also be due to the fact that populations from other anthropized environments maintained high metabolite diversity as the bioactivities of these compounds are likely important in these ecological niches. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol 3‐kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is pivotal in various cancers, including T‐cell acute lymphoblastic leukaemia (T‐ALL), a particularly aggressive type of leukaemia. This study investigates the effects of Neosetophomone B (NSP‐B), a meroterpenoid fungal metabolite, on T‐ALL cell lines, focusing on its anti‐cancer mechanisms and therapeutic potential. NSP‐B significantly inhibited the proliferation of T‐ALL cells by inducing G0/G1 cell cycle arrest and promoting caspase‐dependent apoptosis. Additionally, NSP‐B led to the dephosphorylation and subsequent inactivation of the PI3K/AKT/mTOR signalling pathway, a critical pathway in cell survival and growth. Molecular docking studies revealed a strong binding affinity of NSP‐B to the active site of AKT, primarily involving key residues crucial for its activity. Interestingly, NSP‐B treatment also induced apoptosis and significantly reduced proliferation in phytohemagglutinin‐activated primary human CD3+ T cells, accompanied by a G0/G1 cell cycle arrest. Importantly, NSP‐B did not affect normal primary T cells, indicating a degree of selectivity in its action, targeting only T‐ALL cells and activated T cells. In conclusion, our findings highlight the potential of NSP‐B as a novel therapeutic agent for T‐ALL, specifically targeting the aberrantly activated PI3K/AKT/mTOR pathway and being selective in action. These results provide a strong basis for further investigation into NSP‐B's anti‐cancer properties and potential application in T‐ALL clinical therapies. [ABSTRACT FROM AUTHOR]

Natural products, especially fungal secondary metabolites, have been served as valuable sources of drug leads in pharmaceutical industry. Medicinal plants-associated endophytic fungi possess a well-developed secondary metabolism. In this study, chemical investigation on Penicillium ochrochloron YT2022-65, an endophytic fungus associated with Lonicera Japonica, led to the isolation of six structurally diversified indole alkaloids, including a new one, namely peniochroloid A (1), as well as five previously reported alkaloids, flavonoid B (2), brocaeloid C (3), isoroquefortine C (4), roquefortine C (5), and dihydrocarneamide A (6). Their structures, including the absolute configuration of 1, were determined by a combined analysis of HRESIMS, NMR spectroscopic data, and calculation of the optical rotation. Their cytotoxicity against A549, HepG2, MCF-7, and THP-1 cell lines were evaluated in vitro. The new compound 1 was found to possess considerable cytotoxicity against MCF-7 and THP-1 cell lines with IC50 values of 10.2 and 11.0 μM, respectively. [ABSTRACT FROM AUTHOR]

Marine fungi are promising sources of bioactive natural products. The harsh marine conditions favour the production of natural products with unique structures and functions. The different classes of bioactive metabolites produced by these marine fungi can exhibit cytotoxic, apoptotic, anti-proliferative, antiangiogenic, and autophagy inducing effects on a plethora of cancer cell lines. This review, based on research articles that have been published from 2002 to 2023, provides a concise overview of the anticancer properties of metabolites from marine Aspergillus fungal species. A total of 204 papers are reviewed and 208 most active cytotoxic molecules are reported from Aspergillus. The source as well as the growth medium utilised for the production of cytotoxic metabolites are listed. The mechanism of action of some compounds, which could be used as potential drugs, is also reported. These fungi, under optimal growth conditions, have immense potential as anticancer agents, produce novel metabolites with specific structures that can kill a panel of human cancer cells. However, there is a dire need for more clinical trials and understanding of the mechanisms of action of pharmacologically active constituent. Research should also target how to improve culture methods and perform clinical research on human subjects with more scientific reproducibility. [ABSTRACT FROM AUTHOR]

The filamentous fungus Aspergillus oryzae has a long tradition in East Asian food processing. It is therefore not surprising that in recent years fermentation products of A. oryzae have attracted attention in the emerging field of postbiotics. This review aims to provide a comprehensive summary of the potential postbiotic effects of fermentation products from A. oryzae , by discussing possible mechanisms of action against the background of the molecular composition determined so far. In particular, cell wall constituents, enzymes, extracellular polymeric substances, and various metabolites found in A. oryzae fermentation preparations are described in detail. With reference to the generally assumed key targets of postbiotics, their putative beneficial bioactivities in modulating the microbiota, improving epithelial barrier function, influencing immune responses, metabolic reactions and signaling through the nervous system are assessed. Drawing on existing literature and case studies, we highlight A. oryzae as a promising source of postbiotics, particularly in the context of animal health and nutrition. Challenges and opportunities in quality control are also addressed, with a focus on the necessity for standardized methods to fully harness the potential of fungal-based postbiotics. Overall, this article sheds light on the emerging field of A. oryzae -derived postbiotics and emphasizes the need for further research to fully realize their therapeutic potential. [ABSTRACT FROM AUTHOR]

This study developed and validated a robust UPLC-MS/MS method for quantifying cyclic glycine–proline (cGP) in mangrove-derived Penicillium and Aspergillus strains. The method demonstrated excellent linearity, precision, and recovery, with detection limits as low as 4.8 ng/mL. Penicillium pedernalense extract achieved a cGP content of 67.45 ± 1.11 ng/mL, with a corresponding fermentation yield of 29.31 ± 0.61 mg/L. This surpassed Penicillium steckii, which reached a content of 31.71 ± 0.31 ng/mL, with a yield of 8.51 ± 0.15 mg/L. This quantitative approach for metabolite analysis provides a viable method for screening these fungal strains, highlighting their potential for sustainable production of cyclic glycine–proline (cGP). [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is a neurodegenerative disease that has no cure. The drugs used to treat Alzheimer's disease are based on the inhibition of the enzyme acetylcholinesterase (AChE). In this sense, marine fungal metabolites represent an alternative source for the discovery of drugs based on AChE inhibition (IAChE). The present research carried out a bioprospecting study of marine fungi with acetylcholinesterase inhibition potential. Results: A total of 17 marine fungi were isolated from three stony corals from the Veracruz Reef System. The fungal genera identified were Geotrichum, Curvularia, Penicillium, Aspergillus, and Daldinia. The IAChE was evaluated from the broth and biomass extracts of each fungal strain. As a result, Daldinia eschscholtzii was one of the three fungi with the greatest IAChE effect (32.7%). Subsequently, a bio-directed chromatographic purification of the methanolic extract of the biomass of D. eschscholtzii was carried out. The FRL8.1 fraction was the most active with an IAChE of 41.0%, a value close to Galantamine positive control (44.0%). Furthermore, compound analysis was carried out by GC-MS. Finally, it was determined that the metabolites responsible for the inhibitory effect are probably 4,7-dihydroxycoumarin and 5-nitro-2-naphthalenamine, which was demonstrated by their interactions with the AChE enzyme receptor through molecular docking studies. Conclusions: Coral-associated marine fungi produce secondary metabolites that inhibit acetylcholinesterase. This is the first report of D. eschscholtzii isolated from the stony coral Siderastrea siderea. Finally, we consider that more studies are needed to demonstrate the IAChE potential of marine fungi associated with corals or other marine organisms. [ABSTRACT FROM AUTHOR]

• Fungal metabolites and nanoparticles suppress disease severity. • Fungal metabolites and nanoparticles reduced oxidative stress in tomato plants. • These treatments positively regulate microbial communities in the soil. • Microbial communities showed more abundance by the application of fungal metabolites and nanoparticles. Numerous techniques have been adopted to promote crop growth and improve the effectiveness of biological control. One of these strategies includes the utilization of antimicrobial metabolites from biocontrol agents combined with other strategies. Nanotechnology is a novel and emerging trend in controlling plant diseases. The present study aimed to improve the understanding through an assessment of the mechanism of how the co-application of nanoparticles (SiNPS) and fungal metabolites prevent tomato bacterial wilt infection and explore how the applied treatments regulate the soil microbial community structures present in the rhizosphere of tomato plants. It was demonstrated under in-vitro conditions that the silicon nanoparticles and metabolites of fungi restricted the growth of Ralstonia solanacearum , the causal agent of bacterial wilt. The combined application of nanoparticles and fungal metabolites during planta investigation significantly reduced the disease severity and improved plant growth. These treatments caused significant changes in rhizosphere microbial communities and enhanced the abundance of plant-beneficial microbes. The results of the current study hence advocate the application of fungal metabolites and SiNPS as an effective and environment-friendly strategy for controlling the wilt disease of bacteria in tomato plants and various other host crops. [ABSTRACT FROM AUTHOR]

The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment. [Display omitted] • A comprehensive map of the small intestinal two-front nutrient supply environment • Characterization of spatiotemporal dynamics and cell-type tropism in nutrient absorption • Two nutrient supplies differentially configure the functional zonation of enterocytes • Breakfast skipping exacerbates metabolic diseases by inducing epithelial lipid absorption Spatiotemporal mapping of the environment of the mouse small intestine enables the examination of how circulating metabolites and dietary and gut microbial metabolites contribute to aspects of host metabolism and intestinal physiology. [ABSTRACT FROM AUTHOR]

Screening for new bioactive microbial metabolites, we found a novel okaramine derivative, for which we propose the trivial name lemmokaramine, as well as two already known okaramine congeners – okaramine H and okaramine J - responsible for antimicrobial activity of the recently described microscopic filamentous fungus, Keratinophyton lemmensii BiMM-F76 (= CCF 6359). In addition, two novel substances, a new cyclohexyl denominated lemmensihexol and a new tetrahydroxypyrane denominated lemmensipyrane, were purified and characterized. The compounds were isolated from the culture extract of the fungus grown on modified yeast extract sucrose medium by means of flash chromatography followed by preparative HPLC. The chemical structures were elucidated by NMR and LC-MS. The new okaramine (lemmokaramine) exerted antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and fungi and anticancer activity against different mammalian cell lines (Caco-2, HCT116, HT29, SW480, MCM G1, and MCM DLN). Furthermore, we found a significant antioxidant effect of lemmokaramine following H2O2 treatment indicated by activation of the Nrf2 pathway. This is the first report describing analysis and structural elucidation of bioactive metabolites for the onygenalean genus Keratinophyton. [ABSTRACT FROM AUTHOR]

The document discusses the historical impact of naturally sourced biomolecules in biomedical applications, particularly in the treatment of chronic diseases like diabetes, non-healing wounds, fibrosis, and neurodegeneration. It highlights the potential of plant-derived bioactive compounds, fungal products, peptides, and polysaccharides in addressing chronic diseases through various mechanisms. The review articles featured in the Special Issue provide valuable insights into the use of natural biomolecules for therapeutic interventions and emphasize the need for further research in this promising field. [Extracted from the article]

Garcinia gummi-gutta, commonly known as Garcinia cambogia (syn.), is a popular traditional herbal medicine known for its role in treating obesity, and has been incorporated into several nutraceuticals globally for this purpose. The fruit rind is also used as a food preservative and a condiment because of its high content of hydroxycitric acid, which imparts a sharp, sour flavour. This review highlights the major bioactive compounds present in the tree Garcinia gummi-gutta, with particular emphasis on (2S, 3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acid, commonly referred to as garcinia acid. This acid can be isolated in large amounts through a simple procedure. Additionally, it explores the synthetic transformations of garcinia acid into biologically potent and functionally useful enantiopure compounds, a relatively under-documented area in the literature. This acid, with its six-carbon skeleton, a γ-butyrolactone moiety, and two chiral centres bearing chemically amenable functional groups, offers a versatile framework as a chiron for the construction of diverse molecules of both natural and synthetic origin. The synthesis of chiral 3-substituted and 3,4-disubstituted pyrrolidine-2,5-diones, analogues of the Quararibea metabolite—a chiral enolic-γ-lactone; the concave bislactone skeletons of fungal metabolites (+)-avenaciolide and (−)-canadensolide; the structural skeletons of the furo[2,3-b]furanol part of the anti-HIV drug Darunavir; (−)-tetrahydropyrrolo[2,1-a]isoquinolinones, an analogue of (−)-crispine A; (−)-hexahydroindolizino[8,7-b]indolones, an analogue of the naturally occurring (−)-harmicine; and furo[2,3-b]pyrroles are presented here. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mycotoxin surveys play an essential role in our food safety system. The obtained occurrence data form the basis for the assessment of the exposure of humans and animals to these toxic fungal secondary metabolites. Liquid chromatography coupled with tandem mass spectrometry (LC‐MS/MS) has become the gold standard for mycotoxin determination because it enables selective and sensitive multi‐toxin analysis. Simultaneous determination of several hundreds of secondary fungal metabolites is feasible using this technique. In this study, we combined a targeted dilute‐and‐shoot LC‐MS/MS‐based multi‐analyte approach with multivariate statistics for the analysis of Austrian wheat from two different years and different geographical origins. RESULTS: We quantified 47 secondary fungal metabolites, including regulated emerging and masked mycotoxins. The resulting multi‐mycotoxin occurrence data were further analyzed using both multivariate and univariate statistics. Principal component analysis (PCA) and analysis of variance (ANOVA) simultaneous component analysis (ASCA) were employed to identify regional and yearly trends within the dataset and to quantify the variance in metabolite occurrence attributed to the different effects. In addition, secondary fungal metabolites significantly impacted by these factors were selected via ANOVA. Of the 47 secondary metabolites identified, 39 were affected by the year, region or a combined effect. Moreover, our findings show that 43 of the secondary fungal metabolites were significantly influenced by the weather conditions. CONCLUSION: The results presented in this study underline the added value of combining targeted LC‐MS/MS with multivariate statistics for monitoring a broad spectrum of secondary fungal metabolites in food crops. Through multivariate statistics, trends associated with the year or region can be readily studied. The approach presented could pave the way for a better understanding of the impact of climate change on plant pathogenic fungi and its implications for food safety. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Endophytic fungi are promising producers of phenolic compounds; however, the process of extracting these molecules from the culture medium is a crucial step for obtaining these metabolites. In this context, the best conditions for extracting phenolic compounds produced by Cophinforma mamane CF2-13, isolated from an Amazonian plant, were evaluated. The fungus was cultivated in a liquid medium to obtain its metabolites. The effects of the solvent, time, and temperature were investigated, as well as the use of ultrasound. The total phenolics and the antioxidant activity were assessed to define the best extraction conditions. The optimized extract was chemically characterized and used to analyze its potential in protecting olive oil from lipid oxidation. The best results were found using ethyl acetate at 20 °C for 2 h. These conditions led to 61.61 mg GAEq/g of extract of total phenolics, and an antioxidant capacity of 0.47, 0.45, and 0.29 mmol TEq/g of extract using the DPPH, ABTS, and FRAP methods, respectively. In addition, the optimized extract presented caffeic acid and was able to delay the lipid oxidation of olive oil. The potential of endophytic fungi to produce phenolic compounds is promising for the food industry since natural bioactive compounds have many benefits for human health. [ABSTRACT FROM AUTHOR]

Dyslipidaemia describes the condition of abnormal lipid levels in a person's bloodstream. Since the 1980s, statin medications have been used to treat dyslipidaemia and other comorbidities, such as stroke risk and atherosclerosis. Statin medications were initially synthesised from fungal metabolites, but many synthetic statin drugs have been manufactured since then. Statin medication is quite effective in reducing total cholesterol levels in the bloodstream, but it has limitations. Due to their poor water solubility, statin drugs possess poor oral bioavailability, which hinders their therapeutic efficacy. Nanoparticle drug delivery technology has been shown to improve the pharmacokinetic profiles of many drug classes, and statins have great potential to benefit from this. This paper reviewed the currently available literature on nanoparticle statin medication and evaluated the possible improvements that can be made to the pharmacokinetic profile and efficacy of conventional statin medication. It was found that the oral bioavailability of nanoparticle medication consistently outperformed conventional medication by up to 400% in some cases. Substantial improvements in time to peak plasma concentration and plasma concentration peaks were also found, and increased periods in circulation before excretion were shown. It was concluded that nanoparticle technology has the potential to completely replace conventional statin medication as it offers more significant benefits with minimal drawbacks. Upon further study and development, the manufacture of nanoparticle statin medication should become feasible enough for large-scale application, which will significantly benefit patients and unburden healthcare systems. [ABSTRACT FROM AUTHOR]

Abstract Screening for new bioactive microbial metabolites, we found a novel okaramine derivative, for which we propose the trivial name lemmokaramine, as well as two already known okaramine congeners – okaramine H and okaramine J - responsible for antimicrobial activity of the recently described microscopic filamentous fungus, Keratinophyton lemmensii BiMM-F76 (= CCF 6359). In addition, two novel substances, a new cyclohexyl denominated lemmensihexol and a new tetrahydroxypyrane denominated lemmensipyrane, were purified and characterized. The compounds were isolated from the culture extract of the fungus grown on modified yeast extract sucrose medium by means of flash chromatography followed by preparative HPLC. The chemical structures were elucidated by NMR and LC-MS. The new okaramine (lemmokaramine) exerted antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and fungi and anticancer activity against different mammalian cell lines (Caco-2, HCT116, HT29, SW480, MCM G1, and MCM DLN). Furthermore, we found a significant antioxidant effect of lemmokaramine following H2O2 treatment indicated by activation of the Nrf2 pathway. This is the first report describing analysis and structural elucidation of bioactive metabolites for the onygenalean genus Keratinophyton.

This study aimed to explore the diversity of metabolites and compare the metabolite profiles of Fuzhuan brick teas from Hunan and Shaanxi, to find out the difference in chemical components between fresh tea leaves and Fuzhuan brick tea and to identify the metabolites from fungi in Fuzhuan brick tea. Metabolomic studies on fresh tea leaf samples, Hunan and Shaanxi Fuzhuan brick teas and fungi from them were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and molecular networks of characteristic metabolites. The results showed no significant difference between Hunan and Shaanxi samples in the diversity or profile of metabolites. However, the diversity of metabolites significantly increased as fresh tea leaves were processed into Fuzhuan brick tea, with a decrease in the contents of flavan-3-ols, alkaloids, most amino acids and their derivatives being observed, as well as an increase in the contents of lysophosphatidylcholines (LPCs) and fatty acids, which was accompanied by the appearance of a rich variety of fungal metabolites. Among them, the typical ones included isopentenyl cyclic dipeptides, isopentenyl benzaldehydes, whose existence enriched the diversity of metabolites in Fuzhuan brick tea.

In this overview, naturally occurring resorcylic lactones biosynthetically derived from alternariol and almost exclusively produced by fungi, are discussed with view on their isolation, structure, biological activities, biosynthesis, and total syntheses. This class of compounds consists until now of 127 naturally occurring compounds, with very divers structural motifs. Although only a handful of these toxins (i.e., alternariol and its 9-O-methyl ether, altenusin, dehydroaltenusin, altertenuol, and altenuene) were frequently found and isolated as fungal contaminants in food and feed and have been investigated in significant detail, further metabolites, which were much more rarely found as natural products, similarly show interesting biological activities.

The emerging threat of antibiotic resistance and the formation of resilient biofilms pose a challenge to contemporary healthcare systems. This review dives into the interplay between antibiotic resistance mechanisms and biofilm production. Many pathogenic bacteria have an inherent ability of adhering tightly to a surface forming a complex matrix of extracellular polymeric substances (EPS) surrounding their cells. This is called a biofilm which allows pathogenic bacteria to survive in unsuitable environment. The adaptive nature of biofilms provides a protective shield against conventional antimicrobial agents, promoting chronic infections and complicating medical interventions. This phenomenon further adds to the ever-increasing problem of antibiotic resistance. Thus, there is an immediate necessity in developing novel strategies to deal with bacterial biofilms. In terms of human health, biofilms can be formed on mucosal surfaces and on surfaces of medical equipment. They are also a major reason for causing ‘biofouling’. Different approaches have been undertaken to counteract the menace of biofilms encompassing physical, chemical as well as biological methods. However, recent studies have shown that natural bioactive compounds found in fungal extracts, which has already been gaining attention due to their various properties like immunomodulatory activity, anti-tumor activity, antimicrobial activity etc., have the ability to prevent the formation as well as viability of biofilms through numerous mechanisms. This article thus explores the nuances of biofilm formation and its effects, and further delves deep into the convincing potential of the different components in fungal extracts against bacterial biofilms.

Verticillins are epipolythiodioxopiperazine (ETP) alkaloids, many of which possess potent, nanomolar-level cytotoxicity against a variety of cancer cell lines. Over the last decade, their in vivo activity and mode of action have been explored in detail. Notably, recent studies have indicated that these compounds may be selective inhibitors of histone methyltransferases (HMTases) that alter the epigenome and modify targets that play a crucial role in apoptosis, altering immune cell recognition, and generating reactive oxygen species. Verticillin A (1) was the first of 27 analogues reported from fungal cultures since 1970. Subsequent genome sequencing identified the biosynthetic gene cluster responsible for producing verticillins, allowing a putative pathway to be proposed. Further, molecular sequencing played a pivotal role in clarifying the taxonomic characterization of verticillin-producing fungi, suggesting that most producing strains belong to the genus Clonostachys (i.e., Bionectria), Bionectriaceae. Recent studies have explored the total synthesis of these molecules and the generation of analogues via both semisynthetic and precursor-directed biosynthetic approaches. In addition, nanoparticles have been used to deliver these molecules, which, like many natural products, possess challenging solubility profiles. This review summarizes over 50 years of chemical and biological research on this class of fungal metabolites and offers insights and suggestions on future opportunities to push these compounds into pre-clinical and clinical development. [ABSTRACT FROM AUTHOR]

Maize grain samples collected from 129 small-scale farmers' stores in southern and southwestern Ethiopia were analysed by LC-MS/MS for a total of 218 mycotoxins and other fungal metabolites of which 15% were regulated mycotoxins. Mycotoxins produced by Penicillium, Aspergillus, and Fusarium accounted for 31%, 17%, and 12% of the metabolites, respectively. Most of the current samples were contaminated by masked and/or emerging mycotoxins with moniliformin being the most prevalent one, contaminating 93% of the samples. Each sample was co-contaminated by 3 to 114 mycotoxins/fungal metabolites. Zearalenone, fumonisin B1, and deoxynivalenol were the dominant mycotoxins, occurring in 78%, 61%, and 55% of the samples with mean concentrations of 243, 429, and 530 µg/kg, respectively. The widespread co-occurrence of several mycotoxins in the samples may pose serious health risks due to synergistic/additional effects. [ABSTRACT FROM AUTHOR]

Blue mold caused by Penicillium expansum infection results in severe postharvest deterioration of apples. Salicylic acid (SA) is an effective elicitor of fruit resistance. However, the metabolic mechanism of P. expansum infection of apples and the SA-mediated metabolic responses are still unknown. In this study, the metabolite changes during P. expansum infection of apples and SA-mediated disease resistance were explored by performing ultra-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry. A total of 472 different metabolites were identified between the five groups of sample comparisons, and the correlated metabolic pathways were revealed by bioinformatics analysis. The upregulation of the tricarboxylic acid (TCA) cycle, galactose metabolism, and starch and sucrose metabolism reflected energy conversion for P. expansum invasion and fruit disease resistance. Changes in glyoxylate and dicarboxylate metabolism and carbapenem biosynthesis reflected the biosynthesis of virulence factors and secondary metabolites for fungal infection. Metabolic pathways related to apple natural disease resistance mainly included the upregulation of secondary metabolite biosynthesis and sphingolipid metabolism. SA promoted the TCA cycle, reactive oxygen metabolism, and secondary metabolite biosynthesis of apples for disease resistance. This study revealed the metabolic pathways of P. expansum infection of apples and SA-mediated disease resistance, which helps to improve the understanding of the pathogenic mechanism and disease control. [ABSTRACT FROM AUTHOR]

Introduction: Parasites can facilitate their own spread and reproduction by manipulating insect hosts behavior, as seen in the interaction between Thitarodes xiaojinensis and Ophiocordyceps sinensis. Infection by O. sinensis leads to the mummification of T. xiaojinensis larvae, but the underlying mechanisms remain mysterious. Methods: The morphology of O. sinensis infected larvae and fungal growth were first observed. Subsequently, the metabolite changes in the larvae before and after infection with the fungus were analyzed by LC/MS and targeted metabolomics. The expression of mannitol-related genes was detected using RT-qPCR, and morphological changes in larvae were observed after injection of different concentrations of mannitol into the O. sinensis-infected larvae. Results: Significant changes were found in phenotype, fungal morphology in hemocoel, larval hardness, and mannitol metabolites in infected, mummified 0 h larvae and larvae 5 days after mummification behavior. Surprisingly, the occurrence of mummification behavior was accompanied by fungal dimorphism, as well as the absence of mannitol in both infected and non-infected larvae, until the initial accumulation of mannitol and the expression of mannitol-associated genes occurred at the time ofmummification behavior. The presence of mannitol may promote fungal dimorphism to mediate changes in fungal toxicity or resistance, leading to the end of the fungus-insect coexistence period and the incidence of mummification behavior. Furthermore, mannitol injections increase the mummification rate of the infected larvae without significant difference from the normal mummification phenotype. Discussion: This finding suggests the importance of mannitol in the mummification of host larvae infected with O. sinensis. [ABSTRACT FROM AUTHOR]

Edible mushrooms are not only a valued culinary ingredient but also have several potential medicinal and industrial applications. They are a rich source of protein, fiber, vitamins, minerals, and bioactive compounds such as polysaccharides and terpenoids, and thus have the capacity to support human health. Some species have been shown to have antioxidant, anti-inflammatory, anticancer, and immunomodulatory properties. We have therefore attempted to summarize the potential properties of the edible mushrooms popular in Poland, in the Roztocze area. [ABSTRACT FROM AUTHOR]

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Ochratoxin A is a foreign substance of natural origin. It can be found in a wide range of commodities, including animal feed. Ochratoxin A is a dangerous contaminant, which can have a negative effect on the health and production of animals. In this study, the incidence of ochratoxin A in a complete feed for broilers (n = 25) and pigs (n = 6) was determined. Ochratoxin A was detected in one sample of pigs feed (16.67 %) and its concentration was 1.221 µg.kg−1. This mycotoxin was not detected in the broiler feed samples. These results indicate that the feed samples collected were safe and do not pose a risk of acute mycotoxicosis in animals. [ABSTRACT FROM AUTHOR]

Dothiorella species are fungal plant pathogens associated with Botryosphaeria dieback of grapevine. Symptoms caused by these fungi on grapevines suggest possible implication of phytotoxic metabolites in the infection mechanisms. However, few studies were conducted to investigate the secondary metabolism of these fungi. In this study, 6-methylpyridione analogues were isolated and identified for the first time in liquid cultures of Dothiorella sarmentorum isolated from symptomatic grapevine in Algeria. [ABSTRACT FROM AUTHOR]

Fungi are rich sources of secondary metabolites of agrochemical, pharmaceutical, and food importance, such as mycotoxins, antibiotics, and antitumor agents. Secondary metabolites play vital roles in fungal pathogenesis, growth and development, oxidative status modulation, and adaptation/resistance to various environmental stresses. LaeA contains an S-adenosylmethionine binding site and displays methyltransferase activity. The members of velvet proteins include VeA, VelB, VelC, VelD and VosA for each member with a velvet domain. LaeA and velvet proteins can form multimeric complexes such as VosA-VelB and VelB-VeA-LaeA. They belong to global regulators and are mainly impacted by light. One of their most important functions is to regulate gene expressions that are responsible for secondary metabolite biosynthesis. The aim of this mini-review is to represent the newest cognition of the biosynthetic regulation of mycotoxins and other fungal secondary metabolites by LaeA and velvet proteins. In most cases, LaeA and velvet proteins positively regulate production of fungal secondary metabolites. The regulated fungal species mainly belong to the toxigenic fungi from the genera of Alternaria, Aspergillus, Botrytis, Fusarium, Magnaporthe, Monascus, and Penicillium for the production of mycotoxins. We can control secondary metabolite production to inhibit the production of harmful mycotoxins while promoting the production of useful metabolites by global regulation of LaeA and velvet proteins in fungi. Furthermore, the regulation by LaeA and velvet proteins should be a practical strategy in activating silent biosynthetic gene clusters (BGCs) in fungi to obtain previously undiscovered metabolites. [ABSTRACT FROM AUTHOR]

This article discusses the use of filamentous fungi as industrial strains for the production of high-value compounds. Filamentous fungi, such as Aspergillus oryzae and Trametes versicolor, have shown great potential in synthesizing secondary metabolites, producing proteins, and enhancing enzyme production. Genetic engineering and genome editing have played a significant role in developing efficient production strains. The article also explores strategies for the development of fungal biofactories, including classical and recent methods for strain improvement. Additionally, the role of -omics technologies in understanding fungal biology and optimizing fungal strains for specific industrial applications is discussed. Overall, the article highlights the efforts of the scientific community to develop sustainable filamentous fungal strains for industrial purposes. [Extracted from the article]

Secondary metabolites produced by fungi are well known for their biological properties, which play important roles in medicine. These metabolites aid in managing infections and treating chronic illnesses, thereby contributing substantially to human health improvement. Despite this extensive knowledge, the vast biodiversity and biosynthetic potential of fungi is still largely unexplored, highlighting the need for further research in natural products. In this review, several secondary metabolites of fungal origin are described, emphasizing novel structures and skeletons. The detection and characterization of these metabolites have been significantly facilitated by advancements in analytical systems, particularly modern hyphenated liquid chromatography/mass spectrometry. These improvements have primarily enhanced sensitivity, resolution, and analysis flow velocity. Since the in vitro production of novel metabolites is often lower than the re-isolation of known metabolites, understanding chromatin-based alterations in fungal gene expression can elucidate potential pathways for discovering new metabolites. Several protocols for inducing metabolite production from different strains are discussed, demonstrating the need for uniformity in experimental procedures to achieve consistent biosynthetic activation. [ABSTRACT FROM AUTHOR]

Mycotoxins are secondary fungal metabolites harmful to humans and animals. Patulin (PAT) is a toxin found in different food products but especially in apples and their derivative products. The most common fungi producers of this compound are Aspergillus clavatus and Penicillium expansum. The production of patulin, as other mycotoxins, can be impacted by diverse phenomena such as water and nutrient availability, UV exposure, and the presence of antagonistic organisms. Consequently, gaining a comprehensive understanding of climate and environmental conditions is a crucial step in combating patulin contamination. In this study, moulds were isolated from 40 apple samples collected from seven locations across Hungary: Csenger, Damak, Pallag, Lövőpetri, Nagykálló, and Újfehértó. A total of 183 moulds were morphologically identified, with 67 isolates belonging to the Alternaria, 45 to the Aspergillus, and 13 to the Penicillium groups. The location possessed a higher influence than farming method on the distribution of mould genera. Despite the requirement of higher temperature, Aspergillus species dominated only for the region of Újfehértó with approximately 50% of the isolates belonging to the genus. Four of the seven locations assessed: Csenger, Debrecen-Pallag, Nyírtass and Nagykálló, were dominated by Alternaria species. All isolates belonging to the genera Aspergillus and Penicillium were tested for the presence of the isoepoxidone dehydrogenase (idh) gene, a key player in the patulin metabolic pathway. To guarantee patulin production, this ability was confirmed with TLC assays. The only Aspergillus strain that presented a positive result was the strain Aspergillus clavatus B9/6, originated from the apple cultivar Golden Reinders grown in Debrecen-Pallag by integrated farming. Of the Penicillium isolates only one strain, B10/6, presented a band of the right size (500-600 bp) for the idh gene. Further sequencing of the ITS gene showed that this strain should be classified as Talaromyces pinophilus. The TLC tests confirmed this microorganism as the only patulin producer under the studied conditions for its cluster. [ABSTRACT FROM AUTHOR]

Challenges exist worldwide for the storage of animal feed, though year-long feeding of livestock is especially difficult in northern climates, including Canada. Usage of silage allows for crops to be harvested at the optimal nutritional value and stored for extended periods in customized storage systems. This case study investigated various feed management practices typical of small beef cattle feedlot farms in Southwestern Ontario, Canada. Crop samples were collected monthly and analyzed for mycotoxins and fungal secondary metabolites by liquid chromatography mass spectrometry (LC-MS/MS). Stored barley contained modest concentrations of deoxynivalenol and related compounds, as well as near trace amounts of fumonisin. Stored hay contained low concentrations of deoxynivalenol and beauvericin from the field. Hot spots of the Penicillium metabolite citrinin were detected after 7–8 months of storage in barley (39.2 ng g−1). Citrinin was also detected after 7–8 months in hay (16.3–17.5 ng g−1) along with the appearance of trace amounts of other storage toxins, including penitrem A (8.84 ng g−1), griseofulvin (34.8 ng g−1) and sterigmatocystin (14.1–261 ng g−1). This case study was a unique opportunity to use 'citizen science' to observe the onset of postharvest fungi and associated mycotoxins in various storage conditions allowing for the farmer to make necessary modifications before major problems begin. An improved understanding of the storage conditions that foster fungal growth and mycotoxin production in this working farm led to better agronomic practices, ultimately improving feed quality, livestock health, and profitability. [ABSTRACT FROM AUTHOR]

Decalin-containing tetramic acid derivatives, especially 3-decalinoyltetramic acids (3-DTAs), are commonly found as fungal secondary metabolites. Numerous biological activities of this class of compounds, such as antibiotic, antiviral, antifungal, antiplasmodial, and antiprotozoal properties, have been the subject of ongoing research. For this reason, these molecules have attracted a lot of interest from the scientific community and various efforts including semi-synthesis, co-culturing with bacteria and biosynthetic gene sequencing have been made to obtain more derivatives. In this review, 3-DTAs are classified into four major groups based on the absolute configuration of the bicyclic decalin ring. Their biosynthetic pathways, various biological activities, and structure-activity relationship are then introduced. [ABSTRACT FROM AUTHOR]

Since the first years of history, microbial fermentation products such as bread, wine, yogurt and vinegar have always been noteworthy regarding their nutritional and health effects. Similarly, mushrooms have been a valuable food product in point of both nutrition and medicine due to their rich chemical components. Alternatively, filamentous fungi, which can be easier to produce, play an active role in the synthesis of some bioactive compounds, which are also important for health, as well as being rich in protein content. Therefore, this review presents some important bioactive compounds (bioactive peptides, chitin/chitosan, β-glucan, gamma-aminobutyric acid, L-carnitine, ergosterol and fructooligosaccharides) synthesized by fungal strains and their health benefits. In addition, potential probiotic- and prebiotic fungi were researched to determine their effects on gut microbiota. The current uses of fungal based bioactive compounds for cancer treatment were also discussed. The use of fungal strains in the food industry, especially to develop innovative food production, has been seen as promising microorganisms in obtaining healthy and nutritious food. Fungal-based bioactive compounds have various health benefits. Prebiotic fungi play an active role in the regulation of gut microbiota. Anti-tumor effective fungal components will contribute to alternative medicine. Beta-glucan and chitin are the most promising fungal metabolites for cancer treatment. [ABSTRACT FROM AUTHOR]

Fungi-mediated synthesis of Gold nanoparticles (AuNPs) has advantages in: high efficiency, low energy consumption, no need for extra capping and stabilizing agents, simple operation, and easy isolation and purification. Many fungi have been found to synthesize AuNPs inside cells or outside cells, providing different composition and properties of particles when different fungi species or reaction conditions are used. This is good to produce AuNPs with different properties, but may cause challenges to precisely control the particle shape, size, and activities. Besides, low concentrations of substrate and fungal biomass are needed to synthesize small-size particles, limiting the yield of AuNPs in a large scale. To find clues for the development methods to solve these challenges, the reported mechanisms of the fungi-mediated synthesis of AuNPs were summarized. The mechanisms of intracellular AuNPs synthesis are dependent on gold ions absorption by the fungal cell wall via proteins, polysaccharides, or electric absorption, and the reduction of gold ions via enzymes, proteins, and other cytoplasmic redox mediators in the cytoplasm or cell wall. The extracellular synthesis of AuNPs is mainly due to the metabolites outside fungal cells, including proteins, peptides, enzymes, and phenolic metabolites. These mechanisms cause the great diversity of the produced AuNPs in functional groups, element composition, shapes, sizes, and properties. Many methods have been developed to improve the synthesis efficiency by changing: chloroauric acid concentrations, reaction temperature, pH, fungal mass, and reaction time. However, future studies are still required to precisely control the: shape, size, composition, and properties of fungal AuNPs. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to investigate the fungal growth and diversity in the Sabkha marsh. The anti-bacterial properties of the isolated fungi were assessed using an agar disk diffusion assay, and the crude extracts were tested for their anticancer activities. Liquid chromatography-mass spectrometry was employed to identify the active compounds of the fungal secondary metabolites. In-silico studies were conducted to predict the toxicity, pharmacokinetic properties, and safety profiles of the identified compounds. Results: The analysis revealed that the isolated fungi belonged to the Aspergillus species, specifically Aspergillus flavus and Aspergillus niger. The crude extract of A. flavus exhibited significant anticancer activity against various cancer cell lines, while the antifungal activities against pathogenic bacteria varied between the two fungi. Liquid chromatography-mass spectrometry analysis identified several compounds in the fungal isolates. In Aspergillus flavus, the compounds included Aflavinine, Dihydro-24-hydroxyaflavinine, Phomaligin A, Hydroxysydonic acid, Gregatin B, Pulvinulin A, Chrysogine, Aspergillic acid, Aflatoxin B1, and Aflatoxin G1. In Aspergillus niger, the compounds identified were atromentin, fonsecin B, firalenone, rubrofusarin, aurasperone E, aurasperone D, aurasperone C, nigerone, and αβ-dehydrocurvularin. Conclusion: This study demonstrated promising fungal growth and diversity in the Sabkha marsh, with Aspergillus species being the most prevalent. The fungal crude extract showed anticancer activities against various cancer cell lines, while the antifungal activities against pathogenic bacteria varied between the two fungi. Future research should focus on investigating the antimicrobial activities of these fungi against multidrug-resistant bacteria and exploring the genetic changes in bacteria and cancer cells treated with these fungal extracts. Additionally, it is important to test the anticancer activity of the active compounds separately to determine which one is the active agent against cancer cells. This information can be used in drug development trials. [ABSTRACT FROM AUTHOR]

VP30 and VP40 proteins of Ebola and Marburg viruses have been recognized as potential targets for antiviral drug development due to their essential roles in the viral lifecycle. Targeting these proteins could disrupt key stages of the viral replication process, inhibiting the viruses' ability to propagate and cause disease. The current study aims to perform molecular docking and virtual screening on deep-sea fungal metabolites targeting Marburg virus VP40 Dimer, matrix protein VP40 from Ebola virus Sudan, Ebola VP35 Interferon Inhibitory Domain, and VP35 from Marburg virus. The top ten compounds for each protein target were chosen using the glide score. All the compounds obtained indicate a positive binding interaction. Furthermore, AdmetSAR was utilized to investigate the pharmacokinetics of the inhibitors chosen. Gliotoxin was used as a ligand with Marburg virus VP40 Dimer, Austinol with matrix protein VP40 from Ebola virus Sudan, Ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) with Ebola VP35 Interferon Inhibitory Domain, and Dehydroaustinol with VP35 from Marburg virus. MD modeling and MMPBSA studies were used to provide a better understanding of binding behaviors. Pre-clinical experiments can assist validate our in-silico studies and assess whether the molecule can be employed as an anti-viral drug. [ABSTRACT FROM AUTHOR]

Filamentous fungi are prolific producers of bioactive natural products and play a vital role in drug discovery. Yet, their potential cannot be fully exploited since many biosynthetic genes are silent or cryptic under laboratory culture conditions. Several strategies have been applied to activate these genes, with heterologous expression as one of the most promising approaches. However, successful expression and identification of new products are often hindered by host-dependent factors, such as low gene targeting efficiencies, a high metabolite background, or a lack of selection markers. To overcome these challenges, we have constructed a Penicillium crustosum expression host in a pyrG deficient strain by combining the split-marker strategy and CRISPR-Cas9 technology. Deletion of ligD and pcribo improved gene targeting efficiencies and enabled the use of an additional selection marker in P. crustosum. Furthermore, we reduced the secondary metabolite background by inactivation of two highly expressed gene clusters and abolished the formation of the reactive ortho-quinone methide. Finally, we replaced the P. crustosum pigment gene pcr4401 with the commonly used Aspergillus nidulans wA expression site for convenient use of constructs originally designed for A. nidulans in our P. crustosum host strain. As proof of concept, we successfully expressed a single polyketide synthase gene and an entire gene cluster at the P. crustosum wA locus. Resulting transformants were easily detected by their albino phenotype. With this study, we provide a highly efficient platform for heterologous expression of fungal genes. Key points: Construction of a highly efficient Penicillium crustosum heterologous expression host Reduction of secondary metabolite background by genetic dereplication strategy Integration of wA site to provide an alternative host besides Aspergillus nidulans [ABSTRACT FROM AUTHOR]

Fungi are a good source for lead molecules in drug discovery and development. However, many compounds derived from fungi were not evaluated for their bioactivity against economic, agricultural, and public health pests. Twelve fungal secondary metabolites (1-12) were evaluated for herbicidal activity against Silybum marianum and insecticidal activity against Culex pipiens larvae. Among the tested metabolites, brefeldin A (6) and 6-eopxy-4-hydroxy-3-methoxy-5-methyl-cyclohex-2-en-1-one (11) showed potent herbicidal activity against S. marianum with complete inhibition of seed germination at 500 mg L-1. Compound 6 revealed an exceptional herbicidal activity as it caused complete inhibition of root growth and strong reduction in shoot growth (I = 74.5%) and germination (10.0%) at 25 mg L-1. In addition, dehydroaustin (9), phomaxanthone A (4) and deacetylphomaxanthone A (5) displayed a potent toxicity against fourth larval instar of C. pipiens with LC50 values of 3.27, 57.03 and 63.50 mg L-1, respectively. Based on the results of this study, compounds 4-6, 9 and 11 should be developed as natural pesticides. [ABSTRACT FROM AUTHOR]

Black apples are the result of late-stage microbial decomposition after falling to the ground. This phenomenon is highly comparable from year to year, with the filamentous fungus Monilinia fructigena most commonly being the first invader, followed by Penicillium expansum. Motivated by the fact that only little chemistry has been reported from apple microbiomes, we set out to investigate the chemical diversity and potential ecological roles of secondary metabolites (SMs) in a total of 38 black apples. Metabolomics analyses were conducted on either whole apples or small excisions of fungal biomass derived from black apples. Annotation of fungal SMs in black apple extracts was aided by the cultivation of 15 recently isolated fungal strains on 9 different substrates in a One Strain Many Compounds (OSMAC) approach, leading to the identification of 3,319 unique chemical features. Only 6.4% were attributable to known compounds based on analysis of high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS/MS) data using spectral library matching tools. Of the 1,606 features detected in the black apple extracts, 32% could be assigned as fungal-derived, due to their presence in the OSMAC-based training data set. Notably, the detection of several antifungal compounds indicates the importance of such compounds for the invasion of and control of other microbial competitors on apples. In conclusion, the diversity and abundance of microbial SMs on black apples were found to be much higher than that typically observed for other environmental microbiomes. Detection of SMs known to be produced by the six fungal species tested also highlights a succession of fungal growth following the initial invader M. fructigena. [ABSTRACT FROM AUTHOR]

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The malting industry faces a dilemma in which barley, initially containing low deoxynivalenol levels, occasionally exhibits an unexpected increase in deoxynivalenol levels during malting. In the current study, we investigated mycotoxin accumulation and hyphal localization in single kernels from Fusarium head blight infected barley and malt samples which showed an aberrant behavior of deoxynivalenol increases during malting. While deoxynivalenol levels in these bulk barley samples already ranged from <0.20 to 1.27 µg/g, they further increased on average by approximately 500% after malting, along with Fusarium growth. In addition, deoxynivalenol-3-glucoside and 3-acetyl deoxynivalenol levels increased from <0.20 µg/g to the mean levels of 2.47 µg/g and 1.03 µg/g in the bulk malt, respectively. In the investigation of single kernels, results showed that only 7% of barley single kernels (n = 385) had deoxynivalenol >1.00 μg/g, with the maximum level of 35.97 μg/g. However, 31% of malt single kernels contained deoxynivalenol >1.00 μg/g and up to 255.43 μg/g. Deoxynivalenol-3-glucoside and 3-acetyl deoxynivalenol were found in 40% of malt single kernels. Fungal hyphae were observed in the aleurone layer and embryo of barley kernels with deoxynivalenol >10.00 μg/g, in addition to the husk and vascular bundles of kernels with deoxynivalenol <1.00 μg/g. Hyphae spread largely in these tissues following malting, and even into the endosperm and pericarp cavities of extremely high deoxynivalenol kernels (i.e., >100.00 μg/g). [ABSTRACT FROM AUTHOR]

Background: Chronic Myeloid Leukemia (CML) is particularly challenging to treat due to the T315I BCR::ABL1 mutation. Although fungal metabolites are known for their pharmaceutical potential, none are approved for CML. Our study screened approximately 2000 fungal secondary metabolites to discover inhibitors targeting the T315I- BCR::ABL1 mutant protein. Methods: We conducted comprehensive analyses to elucidate the interactions between the T315I-BCR::ABL1 mutant protein and selected fungal metabolites. These analyses included molecular docking, ADMET assessment, molecular dynamics simulations, principal components analysis, exploration of free energy landscapes, and per-residue decomposition. Results: We identified a range of binding affinities for fungal secondary metabolites, from −11.2 kcal/mol to −2.90 kcal/mol, with the co-crystal ponatinib showing a binding affinity of −9.9 kcal/mol. Notably, twenty seven fungal metabolites had affinities ≤ -10.0 kcal/mol, surpassing ponatinib. Eight compounds, including Phellifuropyranone A and Meshimakobnol B, showed favorable drug-likeness. Molecular dynamics parameters, including RMSD, RMSF, Rg, and SASA, confirmed that Phellifuropyranone A and Meshimakobnol B bind stably to the T315I-BCR::ABL1 mutant protein. Additionally, PCA, DCCM, and free energy landscapes analyses validated the consistency of the molecular dynamics parameters. MM/PBSA analysis indicated that Phellifuropyranone A (–22.88 ± 4.28 kcal/mol) and Meshimakobnol B (−25.86 ± 3.51 kcal/mol) bind similarly to ponatinib (−25.54 ± 6.31 kcal/mol). Per-residue decomposition explored residues MET290, VAL299, ILE315, and PHE359 as crucial for binding to the T315I-BCR::ABL1 mutant protein. Conclusions: Phellifuropyranone A and Meshimakobnol B show significant potency as inhibitors of the T315I-BCR::ABL1 mutant protein, comparable to ponatinib. These compounds may serve as effective alternatives or synergistic agents with ponatinib, potentially overcoming drug resistance and improving treatment outcomes in Chronic Myeloid Leukemia.

The filamentous fungus Aspergillus oryzae has a long tradition in East Asian food processing. It is therefore not surprising that in recent years fermentation products of A. oryzae have attracted attention in the emerging field of postbiotics. This review aims to provide a comprehensive summary of the potential postbiotic effects of fermentation products from A. oryzae, by discussing possible mechanisms of action against the background of the molecular composition determined so far. In particular, cell wall constituents, enzymes, extracellular polymeric substances, and various metabolites found in A. oryzae fermentation preparations are described in detail. With reference to the generally assumed key targets of postbiotics, their putative beneficial bioactivities in modulating the microbiota, improving epithelial barrier function, influencing immune responses, metabolic reactions and signaling through the nervous system are assessed. Drawing on existing literature and case studies, we highlight A. oryzae as a promising source of postbiotics, particularly in the context of animal health and nutrition. Challenges and opportunities in quality control are also addressed, with a focus on the necessity for standardized methods to fully harness the potential of fungal-based postbiotics. Overall, this article sheds light on the emerging field of A. oryzae-derived postbiotics and emphasizes the need for further research to fully realize their therapeutic potential.