Marine-derived Aspergillus Research Articles

A butyrolactone derivative from marine-derived fungal strain Aspergillus terreus BTBU20211037

The secondary metabolites of marine-derived fungal strain, Aspergillus terreus BTBU20211037, isolated from Qinhuangdao coast were investigated. Thirteen compounds were isolated and identified, including one new compound, butyrolactone J (1), and twelve known compounds, butyrolactone I (2), butyrolactone VI (3), aspernolide B (4), aspernolide A (5), 7’-hydroxybutyrolactone III (6), methyl asterrate (7), methyl dichloroasterrate (8), sulochrin (9), methyl 6-acetyl-4-methoxy-5,7,8-trihydroxynaphthalene-2-carboxylate (10), serantrypinone (11), alantrypinone (12), and territrem A (13). The structures of the compounds were elucidated by HRESIMS, NMR, and ECD analysis. Compounds 1, 10, and 13 showed inhibitory effects against Staphylococcus aureus ATCC 25923 with minimal inhibitory concentrations of 12.5, 25, and 100 μg/mL, respectively.

Pleiotropically activation of azaphilone biosynthesis by overexpressing a pathway-specific transcription factor in marine-derived Aspergillus terreus RA2905

The genome sequencing of Aspergillus terreus reveals that the vast number of predicted biosynthetic gene clusters have not reflected by the metabolic profile observed under conventional culture conditions. In this study, a silent azaphilone biosynthetic gene cluster was activated by overexpressing a pathway-specific transcription factor gene2642 in marine-derived fungus A. terreus RA2905. Consequently, twenty azaphilone compounds were identified from the OE2642 mutant, including 11 new azaphilones and their precursors, azasperones C−J (1−5, 7−9) and preazasperones A−C (15−17). The structures of those new compounds were unambiguously determined on the basis of NMR and HRESIMS spectra analysis, and the absolute configurations were established depending on ECD calculations. Compounds 1 and 2 were the rarely reported naturally occurring azaphilones with 2-N coupled phenyl-derivative. The bioactivity assay revealed that compounds 18−20 exhibited significant anti-inflammatory activity. Based on the occurrence of diverse intermediates and the putative gene functions, a plausible biosynthetic pathway of these compounds was proposed. The above results demonstrated that overexpression of the pathway-specific transcription factor presents a promising approach for enriching fungal secondary metabolites and accelerating the targeted discovery of novel biosynthetic products.

Significance of research on natural products from marine-derived Aspergillus species as a source against pathogenic bacteria.

Bacterial infections pose a significant clinical burden on global health. The growing incidence of drug-resistant pathogens highlights the critical necessity to identify and isolate bioactive compounds from marine resources. Marine-derived fungi could provide novel lead compounds against pathogenic bacteria. Due to the particularity of the marine environment, Aspergillus species derived from marine sources have proven to be potent producers of bioactive secondary metabolites and have played a considerable role in advancing drug development. This study reviews the structural diversity and activities against pathogenic bacteria of secondary metabolites isolated from marine-derived Aspergillus species over the past 14 years (January 2010-June 2024), and 337 natural products (including 145 new compounds) were described. The structures were divided into five major categories-terpenoids, nitrogen-containing compounds, polyketides, steroids, and other classes. These antimicrobial metabolites will offer lead compounds to the development and innovation of antimicrobial agents.

Recent Discovery of Nitrogen Heterocycles from Marine-Derived Aspergillus Species.

Nitrogen heterocycles have drawn considerable attention because of their structurally novel and significant biological activities. Marine-derived fungi, especially the Aspergillus species, possess unique metabolic pathways to produce secondary metabolites with novel structures and potent biological activities. This review prioritizes the structural diversity and biological activities of nitrogen heterocycles that are produced by marine-derived Aspergillus species from January 2019 to January 2024, and their relevant biological activities. A total of 306 new nitrogen heterocycles, including seven major categories-indole alkaloids, diketopiperazine alkaloids, quinazoline alkaloids, isoquinoline alkaloids pyrrolidine alkaloids, cyclopeptide alkaloids, and other heterocyclic alkaloids-are presented in this review. Among these nitrogen heterocycles, 52 compounds had novel skeleton structures. Remarkably, 103 compounds showed various biological activities, such as cytotoxic, antimicrobial, anti-inflammatory, antifungal, anti-virus, and enzyme-inhibitory activities, and 21 compounds showed potent activities. This paper will guide further investigations into the structural diversity and biological activities of nitrogen heterocycles derived from the Aspergillus species and their potential contributions to the future development of new natural drug products in the medicinal and agricultural fields.

Screening and genetic engineering of marine-derived Aspergillus terreus for high-efficient production of lovastatin

BackgroundLovastatin has widespread applications thanks to its multiple pharmacological effects. Fermentation by filamentous fungi represents the major way of lovastatin production. However, the current lovastatin productivity by fungal fermentation is limited and needs to be improved.ResultsIn this study, the lovastatin-producing strains of Aspergillus terreus from marine environment were screened, and their lovastatin productions were further improved by genetic engineering. Five strains of A. terreus were isolated from various marine environments. Their secondary metabolites were profiled by metabolomics analysis using Ultra Performance Liquid Chromatography–Mass spectrometry (UPLC–MS) with Global Natural Products Social Molecular Networking (GNPS), revealing that the production of secondary metabolites was variable among different strains. Remarkably, the strain of A. terreus MJ106 could principally biosynthesize the target drug lovastatin, which was confirmed by High Performance Liquid Chromatography (HPLC) and gene expression analysis. By one-factor experiment, lactose was found to be the best carbon source for A. terreus MJ106 to produce lovastatin. To improve the lovastatin titer in A. terreus MJ106, genetic engineering was applied to this strain. Firstly, a series of strong promoters was identified by transcriptomic and green fluorescent protein reporter analysis. Then, three selected strong promoters were used to overexpress the transcription factor gene lovE encoding the major transactivator for lov gene cluster expression. The results revealed that compared to A. terreus MJ106, all lovE over-expression mutants exhibited significantly more production of lovastatin and higher gene expression. One of them, LovE-b19, showed the highest lovastatin productivity at a titer of 1512 mg/L, which represents the highest production level reported in A. terreus.ConclusionOur data suggested that combination of strain screen and genetic engineering represents a powerful tool for improving the productivity of fungal secondary metabolites, which could be adopted for large-scale production of lovastatin in marine-derived A. terreus.

Discovery, Identification, and Mode of Action of Phenolics from Marine-Derived Fungus Aspergillus ustus as Antibacterial Wilt Agents.

The bacterial wilt caused by Ralstonia solanacearum seriously affects crop yield and safety and is difficult to control. Biological activity-guided screening led to the isolation of 11 phenolic compounds including three undescribed compounds (carnemycin H-I and stromemycin B) from the secondary metabolites of a marine-derived Aspergillus ustus. One new compound is an unusual phenolic dimer. Their structures were elucidated by comprehensive spectroscopic data and J-based configurational analysis. The antibacterial activities of the isolated compounds against R. solanacearum were evaluated. Compound 3 exhibited excellent inhibitory activity with an MIC value of 3 μg/mL, which was comparable to that of streptomycin sulfate. Additionally, 3 significantly changed the morphology and inhibited the activity of succinate dehydrogenase (SDH) to interfere with the growth of R. solanacearum. Molecular docking was conducted to clarify the potential mechanisms of compound 3 with SDH. Further in vivo experiments demonstrated that 3 could remarkably inhibit the occurrence of bacterial wilt on tomatoes.

Long-Term Investigation of Marine-Derived Aspergillus Diversity in the Republic of Korea

Aspergillus species play a crucial role in terrestrial environments as degraders and are well known for producing various secondary metabolites. Recently, Aspergillus species have been discovered in marine environments, exhibiting adaptability to high salinity and producing diverse secondary metabolites with valuable properties. However, limited research has focused on their marine diversity, leading to inaccurate species identification. The current study addresses this gap by investigating diverse marine habitats in the Republic of Korea, including sediment, seawater, seaweed, and marine animals. From three coasts of the Korean Peninsula, 472 Aspergillus strains were isolated from the various marine habitats. A total of 41 species were accurately identified using multigenetic markers: internal transcribed spacer, calmodulin, and β-tubulin. The findings underscore the importance of accurate identification and provide a basis for elucidating the functional role of marine-derived Aspergillus species in marine ecosystems.

Antitumor activity of urease-free l-asparaginase with low glutaminase coactivity produced by marine-derived Aspergillus flavus

l-asparaginase, which has a high therapeutic effect in various cancer diseases, hydrolyzes l-asparagine to aspartate and ammonia and is mainly used in treating Acute Lymphoblastic Leukaemia. This study aims to investigate the l-asparaginase production potential of marine filamentous fungi and the partial purification and characterization of the l-asparaginase. The rapid plate screening method was used to measure the l-asparaginase activity of 94 marine fungi. l-asparaginase producers were then screened for glutaminase and urease activity. The selected extracellular l-asparaginase producer, Aspergillus flavus MF10, showed 2.82 U/mL l-asparaginase activity in small-scale fermentation. l-asparaginase was concentrated by ultrafiltration followed by acetone precipitation. The specific activity of the enzyme, purified 4,8 fold by partial purification, was determined as 259 U/mg. There were no urease and glutaminase activities in the fermentation broth, but low glutaminase activity (1.27 U/mL) was detected in the concentrated fermentation broth. The optimum pH and temperature of the l-asparaginase were 8.0 and 40 °C, respectively. l-asparaginase was stable at pH 7.0–8.0 and can maintain its activity at 70% at 40 °C after 1 h. While the enzyme decreased the viability of SH-SY5Y (neuroblastoma) to 43% and LNCap (prostate cancer) to 61%, it did not show cytotoxic effects in healthy cell line L929 (fibroblast). It was also determined that l-asparaginase showed low cytotoxicity in HaCaT (keratinocyte) cells. In conclusion, it was shown that urease-free l-asparaginase with low glutaminase coactivity, produced from marine-derived A. flavus MF10, has the potential for medical use.

A Pair of New Spirocyclic Alkaloid Enantiomers with TrxR Inhibitory Activities Were Isolated from Marine-Derived Aspergillus ruber TX-M4-1

A Pair of New Spirocyclic Alkaloid Enantiomers with TrxR Inhibitory Activities Were Isolated from Marine-Derived Aspergillus ruber TX-M4-1

Enzymatic Benzofuranoindoline Formation in the Biosynthesis of the Strained Bridgehead Bicyclic Dipeptide (+)-Azonazine A.

We uncovered and reconstituted a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A from marine-derived Aspergillus insulicola. Formation of the hexacyclic benzofuranoindoline ring system from cyclo-(l-Trp-N-methyl-l-Tyr) is catalyzed by a P450 enzyme through an oxidative cyclization. Supplementing the producing strain with various indole-substituted tryptophan derivatives resulted in the generation of a series of azonazine A analogs.

Deciphering Molecular Aspects of Potential α-Glucosidase Inhibitors within Aspergillus terreus: A Computational Odyssey of Molecular Docking-Coupled Dynamics Simulations and Pharmacokinetic Profiling.

Hyperglycemia, as a hallmark of the metabolic malady diabetes mellitus, has been an overwhelming healthcare burden owing to its high rates of comorbidity and mortality, as well as prospective complications affecting different body organs. Available therapeutic agents, with α-glucosidase inhibitors as one of their cornerstone arsenal, control stages of broad glycemia while showing definitive characteristics related to their low clinical efficiency and off-target complications. This has propelled the academia and industrial section into discovering novel and safer candidates. Herein, we provided a thorough computational exploration of identifying candidates from the marine-derived Aspergillus terreus isolates. Combined structural- and ligand-based approaches using a chemical library of 275 metabolites were adopted for pinpointing promising α-glucosidase inhibitors, as well as providing guiding insights for further lead optimization and development. Structure-based virtual screening through escalating precision molecular docking protocol at the α-glucosidase canonical pocket identified 11 promising top-docked hits, with several being superior to the market drug reference, acarbose. Comprehensive ligand-based investigations of these hits' pharmacokinetics ADME profiles, physiochemical characterizations, and obedience to the gold standard Lipinski's rule of five, as well as toxicity and mutagenicity profiling, proceeded. Under explicit conditions, a molecular dynamics simulation identified the top-stable metabolites: butyrolactone VI (SK-44), aspulvinone E (SK-55), butyrolactone I 4''''-sulfate (SK-72), and terrelumamide B (SK-173). They depicted the highest free binding energies and steadiest thermodynamic behavior. Moreover, great structural insights have been revealed, including the advent of an aromatic scaffold-based interaction for ligand-target complex stability. The significance of introducing balanced hydrophobic/polar moieties, like triazole and other bioisosteres of carboxylic acid, has been highlighted across docking, ADME/Tox profiling, and molecular dynamics studies for maximizing binding interactions while assuring safety and optimal pharmacokinetics for targeting the intestinal-localized α-glucosidase enzyme. Overall, this study provided valuable starting points for developing new α-glucosidase inhibitors based on nature-derived unique scaffolds, as well as guidance for prospective lead optimization and development within future pre-clinical and clinical investigations.

Austalide derivative from marine-derived Aspergillus sp. and evaluation of its cytotoxic and ADME/TOPKAT properties.

In-depth chemical investigation of an ethyl acetate extract of Aspergillus sp. isolated from the soft coral Sinularia species resulted in the isolation of one new meroterpenoid, austalide Z (1), one known austalide W (2), six known prenylated indole diketopiperazine alkaloids (3-8), and phthalic acid and its ethyl derivative (9-10). The structures were established by means of 1D and 2D NMR (one- and two-dimensional nuclear magnetic resonance) experiments supported by UV analysis and ESI-MS (electrospray ionization mass spectrometry). In vitro cytotoxic evaluation was performed against the Caco-2 cancer cell line using the MTT assay, which showed that the examined compounds had weak to moderate activities, with the new meroterpenoid austalide Z (1) displaying an IC50 value of 51.6 μg mL-1. ADME/TOPKAT (absorption, distribution, metabolism, excretion, and toxicity) predication performed in silico showed that most of the isolated compounds possessed reasonable pharmacokinetic, pharmacodynamic, and toxicity properties. Thus, it can be concluded that Aspergillus sp. could act as a source of drug leads for cancer prevention with promising pharmacokinetic and pharmacodynamic properties and thus could be incorporated in pharmaceutical dosage forms.

Structural characterization and immunomodulatory activity of an exopolysaccharide from marine-derived Aspergillus versicolor SCAU141

Until now, relatively little is known about marine-derived fungal polysaccharides and their activities. Exopolysaccharide AVP141-A was isolated from the broth of marine-derived fungus Aspergillus versicolor SCAU141 and purified by Diethylaminoethyl-Sepharose Fast Flow and Sephadex G-100. The structural characteristics of AVP141-A was studied by chemical analysis together with high-performance gel permeation chromatography, ion chromatography, Fourier-transform infrared spectroscopy, gas chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. The results showed that AVP141-A with the molecular weight of 5.10 kDa was mainly composed of →4)-α-D-Glcp-(1→, branched by α-D-Glcp-(1→ and →6)-α-D-Glcp-(1→ at C-6 positions of the glucan backbone. In particular, sulfate ester (approximately 3.62 %) was found in AVP141-A, which was frequently considered to occur in marine-derived microbial polysaccharides rather than other microbial polysaccharides. Furthermore, AVP141-A significantly enhanced the activity of the inflammatory factors NO, COX-2 and TNF-α in RAW264.7 macrophages by activating the MAPK/p38 and NF-κB/p65 pathways. In addition, metabolomic analysis revealed that most of the pathways with significant changes in RAW264.7 macrophages treated with AVP141-A were amino acid-related pathways, and arginine was the characteristic metabolite. In conclusion, this study identified AVP141-A as a marine fungus-derived sulfated exopolysaccharide with potential for development as an immune activator.

Investigation on the chemical constituents of the marine-derived fungus strain Aspergillus brunneoviolaceus MF180246

Aspergillus have been proven to be excellent resources for new natural products. During our systematic biodiversifying new compounds from marine derived fungi, one novel compound, asperbrunneo acid (1), along with seven bistetrahydroxanthone analogues, secalonic acid D (2), secalonic acid F (3), secalonic acid F1 (4), secalonic acid H (5), penicillixanthone A (6), chrysoxanthone C (7), and asperdichrome (8), one ketodivinyllactonic steroid, herbarulide (9), as well as one tyrosine-derived compound, aspergillusol A (10), were isolated from the marine-derived fungus Aspergillus brunneoviolaceus MF180246. These structures were elucidated by HRMS, 1 D and 2 D NMR analysis. Compound 1 possessed the first reported new carbon skeleton natural product. Compounds 1, 4, 5, 6, 7 and 8 showed antibacterial activity against Staphylococcus aureus with minimum inhibitory concentration values of 200, 25, 50, 6.25, 50, and 25 µg/ml, respectively.

Research Advances of Bioactive Sesquiterpenoids Isolated from Marine-Derived Aspergillus sp.

Marine fungi Aspergillus sp. is an important source of natural active lead compounds with biological and chemical diversity, of which sesquiterpenoids are an extremely important class of bioactive secondary metabolites. In this paper, we review the sources, chemical structures, bioactivity, biosynthesis, and druggability evaluation of sesquiterpenoids discovered from marine fungi Aspergillus sp. since 2008. The Aspergillus species involved include mainly Aspergillus fumigatus, Aspergillus versicolor, Aspergillus flavus, Aspergillus ustus, Aspergillus sydowii, and so on, which originate from sponges, marine sediments, algae, mangroves, and corals. In recent years, 268 sesquiterpenoids were isolated from secondary metabolites of marine Aspergillus sp., 131 of which displayed bioactivities such as antitumor, antimicrobial, anti-inflammatory, and enzyme inhibitory activity. Furthermore, the main types of active sesquiterpenoids are bisabolanes, followed by drimanes, nitrobenzoyl, etc. Therefore, these novel sesquiterpenoids will provide a large number of potential lead compounds for the development of marine drugs.

Genomic Analysis and Antimicrobial Components of M7, an Aspergillus terreus Strain Derived from the South China Sea.

As a typical filamentous fungus, Aspergillus species are highly adaptive to diverse ecological habitats, represented by their occurrence in both terrestrial and marine environments; this could plausibly be ascribed to their preeminent biological diversity and metabolic variability. In this context, marine-derived Aspergillus fungi have recently attracted great interest as a promising potential source of biologically active compounds. The present study depicts the genomic and chemical profiles of M7, a strain of Aspergillus terreus isolated from mussels in the South China Sea; the crude extracts of its soybean fermentation exhibit potent growth-inhibitory properties against A. baumannii and P. aeruginosa. Subsequently, functional genomics analysis based on sequences implied a considerable biosynthetic potential of the strain, which is substantiated by the 75 biosynthetic gene clusters (BGCs) identified via genome mining; the majority (49 BGCs) were functionally unknown. Representatively, the putative biosynthetic pathways of terramide A and terramide B, the bacteriostatic products obtained through chemical separation and characterized from the fermentation, could not be allocated to any known BGC, highlighting the metabolic potency and diversity of this strain. Meanwhile, based on a comprehensive analysis of fermentation conditions, we confirmed that the presence of environmental iron was inversely correlated with antimicrobial characteristics of the strain M7, presumably due to the interference in the biosynthetic pathway or bioactive mechanisms of the antimicrobial components, e.g., terramide A and B. Our observations provide genomic and biochemical insight into the metabolic and ecological novelties of this strain, underpinning the diversity of biosynthetic flexibility and adaptive strategies of marine Aspergillus fungi.

Versicotide G suppresses osteoclastogenesis and prevents osteolysis

Excessive formation and function of osteoclasts cause various osteolytic bone diseases. Natural products are a potential source for the discovery of new therapeutic candidates to treat bone destruction diseases. In this study, chemical informatics and bioassay guided examination of the marine-derived Aspergillus versicolor F77 fungus chemically resulted in the isolation of seven cyclopeptides, of which versicotides G-J (1–4) are new cyclohexapeptides. Their structures were identified by spectroscopic data in association with Marfey method and single crystal X-ray diffraction data for configurational assignments. Bioassay revealed that versicotide G (1, VG) is the most active among the analogs to suppress the receptor activator of nuclear factor-KB ligand (RANKL)-induced osteoclastogenesis in bone marrow derived monocytes (BMMs) without affecting BMMs viability. VG also suppressed RANKL-induced actin-ring formation and resorbing function of osteoclast dose-dependently. Mechanistically, VG attenuated RANKL-induced intracellular calcium elevation by inhibiting PLCγ1 phosphorylation and blocking the activation of downstream phosphatase calcineurin. In addition, VG abrogated the expression and translocation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), leading to the downregulation of the expression of osteoclast-specific genes and the abolishment of the osteoclast formation. In the in vivo test, VG suppressed osteoclast formation and bone loss in Ti-induced calvarial osteolytic mouse model.These findings imply that VG is a promising candidate for the remedy of bone destruction-related diseases.

Removal process and mechanism of hexavalent chromium by adsorption-coupled reduction with marine-derived Aspergillus niger mycelial pellets

In order to remove hexavalent chromium (Cr(VI)) from solutions efficiently, the mycelial pellets with a marine-derived fungus Aspergillus niger as a biosorbent were prepared. The effects of removal process parameters such as solution pH, initial Cr(VI) concentration and biomass concentration on Cr(VI) removal process were investigated. The results showed that Cr(VI) removal rate up to 100% could be achieved under optimized conditions, which indicated the excellent Cr(VI) removal performance of the Aspergillus niger pellets. As a more important point, the Cr(VI) removal mechanism was studied, and the results revealed that Cr(VI) removal was achieved in the adsorption-coupled reduction process. A little of Cr(VI) was reduced to less toxic trivalent chromium (Cr(III)) in solution, while some was absorbed on the surface of mycelial pellets. Then they may be reduced on the surface or transferred into cells and then be reduced. The marine-derived A. niger mycelial pellets show properties of easy preparation and separation and cost effectiveness, which are potential biosorbent and reductant in the treatment of trace chromate containing wastewater.

Co-biomass degradation of fluoranthene by marine-derived fungi; Aspergillus aculeatus and Mucor irregularis: Comprehensive process optimization, enzyme induction and metabolic analyses

The application and relevance of marine-derived fungi in the mycoremediation of environment polluted with polycyclic aromatic hydrocarbons (PAHs) is promising whilst limiting environmental hazards. The present study investigated the fluoranthene degradation efficiency of marine-derived fungal co-culture, Aspergillus aculeatus (AA) and Mucor irregularis (MI) in batch processes (Plackett-Burman experiments) enhanced with the addition of surfactants and solid-state substrates. Further optimization studies done through fractional factorial design revealed that the co-culture exhibited 98.4% fluoranthene degradation capacity after 7 days of incubation. The role played by enzymes was revealed with 93, 85 and 71% induction of laccase, lignin peroxidase and manganese peroxidase respectively during fluoranthene degradation. The Gas Chromatography-Mass Spectrometry analysis revealed the formation of five metabolites; 1,2- dihydroxyfluoranthene, 9H-fluorene-1,9-dicarboxylic acid, benzene-1,2,4-tricarboxylic acid, benzene-1,3-dicarboxylic acid and benzoic acid after fluoranthene degradation by AA + MI co-culture which was used in predicting a metabolic pathway. The findings of this study elucidated the promising potentials of marine-derived fungal co-biomass in the eco-friendly remediation of polycyclic aromatic hydrocarbons thus promoting green technology.

Enhanced production of terrein in marine-derived Aspergillus terreus by refactoring both global and pathway-specific transcription factors

BackgroundTerrein, a major secondary metabolite from Aspergillus terreus, shows great potentials in biomedical and agricultural applications. However, the low fermentation yield of terrein in wild A. terreus strains limits its industrial applications.ResultsHere, we constructed a cell factory based on the marine-derived A. terreus RA2905, allowing for overproducing terrein by using starch as the sole carbon source. Firstly, the pathway-specific transcription factor TerR was over-expressed under the control of a constitutive gpdA promoter of A. nidulans, resulting in 5 to 16 folds up-regulation in terR transcripts compared to WT. As expected, the titer of terrein was improved in the two tested terR OE mutants when compared to WT. Secondly, the global regulator gene stuA, which was demonstrated to suppress the terrein synthesis in our analysis, was deleted, leading to greatly enhanced production of terrein. In addition, LS-MS/MS analysis showed that deletion of StuA cause decreased synthesis of the major byproduct butyrolactones. To achieve an optimal strain, we further refactored the genetic circuit by combining deletion of stuA and overexpression of terR, a higher terrein yield was achieved with a lower background of byproducts in double mutants. In addition, it was also found that loss of StuA (both ΔstuA and ΔstuA::OEterR) resulted in aconidial morphologies, but a slightly faster growth rate than that of WT.ConclusionOur results demonstrated that refactoring both global and pathway-specific transcription factors (StuA and TerR) provides a high-efficient strategy to enhance terrein production, which could be adopted for large-scale production of terrein or other secondary metabolites in marine-derived filamentous fungi.