Isolation of new lucilactaene derivatives from P450 monooxygenase and aldehyde dehydrogenase knockout Fusarium sp. RK97-94 strains and their biological activities

Abdelhakim, Islam A; Motoyama, Takayuki; Nogawa, Toshihiko; Mahmud, Fauze; Futamura, Yushi; Takahashi, Shunji; Osada, Hiroyuki

doi:10.1038/s41429-022-00529-3

Cited by 4 publications

(4 citation statements)

References 17 publications

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“…The biosynthetic gene cluster of lucilactaene (27) was identified in Fusarium sp. RK 97-94, and a putative biosynthetic pathway was proposed [65,66]. The biosynthetic gene cluster for fusaristatin A (28) was identified in F. graminearum and partially characterized [67].…”

Section: Metabologenomic Analysis-linking Secondary Metabolites To Bg...mentioning

confidence: 99%

Genomic and Metabolomic Analysis of the Endophytic Fungus Fusarium sp. VM-40 Isolated from the Medicinal Plant Vinca minor

Xiao

Iacovelli

et al. 2023

JoF

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The genus Fusarium is well-known to comprise many pathogenic fungi that affect cereal crops worldwide, causing severe damage to agriculture and the economy. In this study, an endophytic fungus designated Fusarium sp. VM-40 was isolated from a healthy specimen of the traditional European medicinal plant Vinca minor. Our morphological characterization and phylogenetic analysis reveal that Fusarium sp. VM-40 is closely related to Fusarium paeoniae, belonging to the F. tricinctum species complex (FTSC), the genomic architecture and secondary metabolite profile of which have not been investigated. Thus, we sequenced the whole genome of Fusarium sp. VM-40 with the new Oxford Nanopore R10.4 flowcells. The assembled genome is 40 Mb in size with a GC content of 47.72%, 15 contigs (≥50,000 bp; N 50~4.3 Mb), and 13,546 protein-coding genes, 691 of which are carbohydrate-active enzyme (CAZyme)-encoding genes. We furthermore predicted a total of 56 biosynthetic gene clusters (BGCs) with antiSMASH, 25 of which showed similarity with known BGCs. In addition, we explored the potential of this fungus to produce secondary metabolites through untargeted metabolomics. Our analyses reveal that this fungus produces structurally diverse secondary metabolites of potential pharmacological relevance (alkaloids, peptides, amides, terpenoids, and quinones). We also employed an epigenetic manipulation method to activate cryptic BGCs, which led to an increased abundance of several known compounds and the identification of several putative new compounds. Taken together, this study provides systematic research on the whole genome sequence, biosynthetic potential, and metabolome of the endophytic fungus Fusarium sp. VM-40.

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Section: Metabologenomic Analysis-linking Secondary Metabolites To Bg...mentioning

confidence: 99%

Genomic and Metabolomic Analysis of the Endophytic Fungus Fusarium sp. VM-40 Isolated from the Medicinal Plant Vinca minor

Xiao

Iacovelli

et al. 2023

JoF

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“…Despite the great potential of microorganisms to produce new secondary metabolites of high therapeutic value, large-scale genome sequencing and bioinformatics studies have revealed that many biosynthetic gene clusters (BGCs) remain silent under typical laboratory conditions. − This limits the effectiveness of conventional isolation methods for discovering novel natural products. To address this challenge, several approaches were developed to activate silent BGCs. , Culturing one microbial strain in various culture conditions including media composition, aeration, culture vessel, or addition of enzyme inhibitors can nonselectively activate silent BGCs; thus more cryptic metabolites could be accessible. , Chemical elicitation of microbial cultures, − coculture, ribosome engineering, manipulation of global regulators, , heterologous expression, , promoter exchange, , gene knockout, and gene cluster refactoring are also used to activate silent BGCs in microorganisms. The expression of cluster-specific regulators also represents a promising approach toward the selective activation of silent BGC and the production of novel natural products …”

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confidence: 99%

“…6,7 Culturing one microbial strain in various culture conditions including media composition, aeration, culture vessel, or addition of enzyme inhibitors can nonselectively activate silent BGCs; thus more cryptic metabolites could be accessible. 8,9 Chemical elicitation of microbial cultures, 10−12 coculture, 13 ribosome engineering, 14 manipulation of global regulators, 15,16 heterologous expression, 17,18 promoter exchange, 19,20 gene knockout, 21 and gene cluster refactoring 22 are also used to activate silent BGCs in microorganisms. The expression of cluster-specific regulators also represents a promising approach toward the selective activation of silent BGC and the production of novel natural products.…”

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confidence: 99%

Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

A. Abdelhakim,

Futamura,

Asami

et al. 2024

J. Nat. Prod.

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Actinomycetes are prolific producers of natural products, particularly antibiotics. However, a significant proportion of its biosynthetic gene clusters (BGCs) remain silent under typical laboratory conditions. This limits the effectiveness of conventional isolation methods for the discovery of novel natural products. Genetic interventions targeting the activation of silent gene clusters are necessary to address this challenge. Streptomyces antibiotic regulatory proteins (SARPs) act as cluster-specific activators and can be used to target silent BGCs for the discovery of new antibiotics. In this study, the expression of a previously uncharacterized SARP protein, Syo_1.56, in Streptomyces sp. RK18-A0406 significantly enhanced the production of known antimycins and led to the discovery of 12 elasnins (1−12), 10 of which were novel. The absolute stereochemistry of elasnin A 1 was assigned for the first time to be 6S. Unexpectedly, Syo_1.56 seems to function as a pleiotropic rather than cluster-specific SARP regulator, with the capability of co-regulating two distinct biosynthetic pathways, simultaneously. All isolated elasnins were active against wild-type and methicillin-resistant Staphylococcus aureus with IC 50 values of 0.5−20 μg/mL, some of which (elasnins A 1 , B 2 , and C 1 and proelasnins A 1 , and C 1 ) demonstrated moderate to strong antimalarial activities against Plasmodium falciparum 3D7. Elasnins A 1 , B 3 , and C 1 also showed in vitro inhibition of the metallo-β-lactamase responsible for the development of highly antibiotic-resistant bacterial strains.

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“…Integracides F, G, H, and J (161-164) were also shown to have stronger anti-leishmanial activity towards L. donovani than the positive control pentamidine (IC 50 = 6.35 µM)[100]. Among twelve lucilactaene derivatives (165-176), compounds 166-168 showed very potent antimalarial activity toward P. falciparum (IC 50 = 0.0015, 0.15, and 0.68 µM, respectively)[101][102][103]. Structure−activity relationship study suggested that epoxide is extremely detrimental, and demethylation of the lucilactaene methyl ester and formation of the free carboxylic acid group resulted in a 300-fold decrease in activity.…”

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confidence: 99%

Fusarium-Derived Secondary Metabolites with Antimicrobial Effects

Huang

Zhu

et al. 2023

Molecules

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Fungal microbes are important in the creation of new drugs, given their unique genetic and metabolic diversity. As one of the most commonly found fungi in nature, Fusarium spp. has been well regarded as a prolific source of secondary metabolites (SMs) with diverse chemical structures and a broad spectrum of biological properties. However, little information is available concerning their derived SMs with antimicrobial effects. By extensive literature search and data analysis, as many as 185 antimicrobial natural products as SMs had been discovered from Fusarium strains by the end of 2022. This review first provides a comprehensive analysis of these substances in terms of various antimicrobial effects, including antibacterial, antifungal, antiviral, and antiparasitic. Future prospects for the efficient discovery of new bioactive SMs from Fusarium strains are also proposed.

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Isolation of new lucilactaene derivatives from P450 monooxygenase and aldehyde dehydrogenase knockout Fusarium sp. RK97-94 strains and their biological activities

Cited by 4 publications

References 17 publications

Genomic and Metabolomic Analysis of the Endophytic Fungus Fusarium sp. VM-40 Isolated from the Medicinal Plant Vinca minor

Genomic and Metabolomic Analysis of the Endophytic Fungus Fusarium sp. VM-40 Isolated from the Medicinal Plant Vinca minor

Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

Fusarium-Derived Secondary Metabolites with Antimicrobial Effects

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