Fungal Endophytes as Efficient Sources of Plant-Derived Bioactive Compounds and Their Prospective Applications in Natural Product Drug Discovery: Insights, Avenues, and Challenges

Fungal endophytes are well-established sources of biologically active natural compounds with many producing pharmacologically valuable specific plant-derived products. This review details typical plant-derived medicinal compounds of several classes, including alkaloids, coumarins, flavonoids, glycosides, lignans, phenylpropanoids, quinones, saponins, terpenoids, and xanthones that are produced by endophytic fungi. This review covers the studies carried out since the first report of taxol biosynthesis by endophytic Taxomyces andreanae in 1993 up to mid-2020. The article also highlights the prospects of endophyte-dependent biosynthesis of such plant-derived pharmacologically active compounds and the bottlenecks in the commercialization of this novel approach in the area of drug discovery. After recent updates in the field of ‘omics’ and ‘one strain many compounds’ (OSMAC) approach, fungal endophytes have emerged as strong unconventional source of such prized products.

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Production of eugenol from fungal endophytesNeopestalotiopsissp. andDiaporthesp. isolated fromCinnamomum loureiroileaves

PeerJ ◽

10.7717/peerj.6427 ◽

2019 ◽

Vol 7 ◽

pp. e6427 ◽

Cited By ~ 5

Author(s):

Chutima Tanapichatsakul ◽

Sarunpron Khruengsai ◽

Sakon Monggoot ◽

Patcharee Pripdeevech

Keyword(s):

Antimicrobial Activity ◽

Antioxidant Activity ◽

Endophytic Fungi ◽

Antioxidant Activities ◽

Chemical Constituents ◽

Fungal Endophytes ◽

Biologically Active ◽

Crude Extracts ◽

Antioxidant Agents ◽

Fungal Extracts

Endophytic fungi, which colonize within a host plant without causing any apparent diseases, have been considered as an important source of bioactive secondary metabolites containing antimicrobial and antioxidant activities. The aim of this research was to isolate the endophytic fungi ofCinnamomum loureiroiand then to screen their antimicrobial and antioxidant activities. A total of 11 fungal endophytes were isolated from healthy leaves ofCinnamomum loureiroibelonging to six genera:Botryosphaeria,Colletotrichum,Diaporthe,Fusarium,Neopestalotiopsis, andPestalotiopsis. All isolated strains were cultured and further extracted with ethyl acetate solvent. Antimicrobial activity of all crude endophytic fungal extracts was analyzed using disc diffusion assay against six bacterial and two fungal pathogens. Crude extracts of strains MFLUCC15-1130 and MFLUCC15-1131 showed broad-spectrum antimicrobial activity against all tested pathogens. Activity againstBacillus cereusandStaphylococcus epidermidiswas notable, showing the lowest minimum inhibitory concentration at 3.91 μg/mL. Antioxidant activity of all crude endophytic fungal extracts was also evaluated based on 2,2-diphenyl-1-picrylhydrazyl assay. Significant antioxidant activity was detected in the crude extracts of fungus MFLUCC15-1130 and MFLUCC15-1131 with IC50of 22.92 ± 0.67 and 37.61 ± 0.49 μg/mL, respectively. Using molecular identification, MFLUCC15-1130 and MFLUCC15-1131 were identified asNeopestalotiopsissp. andDiaporthesp., respectively. The major chemical constituents produced by both crude extracts were identified by gas chromatography-mass spectrometry. Eugenol, myristaldehyde, lauric acid, and caprylic acid were the primary antimicrobial and antioxidant compounds in both crude extracts. This is the first report of eugenol being a biologically active compound ofNeopestalotiopsissp. andDiaporthesp. fungal endophytes. Eugenol has been reported as antimicrobial and antioxidant agents with agronomic applications. Thus the two newly-isolated endophytes may be used for eugenol production, which in turn can be used in a variety of applications.

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Analysis of Five Pharmacologically Active Compounds from Rhodiola for Natural Product Drug Discovery with Capillary Electrophoresis

Chromatographia ◽

10.1365/s10337-004-0415-5 ◽

2004 ◽

Vol 60 (9-10) ◽

pp. 589-595 ◽

Cited By ~ 13

Author(s):

Yourui Suo ◽

Honglun Wang ◽

Yulin Li ◽

Jinmao You ◽

Hanqing Wang

Keyword(s):

Capillary Electrophoresis ◽

Drug Discovery ◽

Natural Product ◽

Active Compounds ◽

Pharmacologically Active ◽

Pharmacologically Active Compounds

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Recent advances in phenotypic drug discovery

F1000Research ◽

10.12688/f1000research.25813.1 ◽

2020 ◽

Vol 9 ◽

pp. 944

Author(s):

David C. Swinney ◽

Jonathan A. Lee

Keyword(s):

Drug Discovery ◽

Muscular Atrophy ◽

Short Review ◽

Medical Needs ◽

Recent Advances ◽

Safety Studies ◽

Pharmacologically Active ◽

Scientific Value ◽

Pharmacologically Active Compounds ◽

Library Selection

There is a great need for innovative new medicines to treat unmet medical needs. The discovery and development of innovative new medicines is extremely difficult, costly, and inefficient. In the last decade, phenotypic drug discovery (PDD) was reintroduced as a strategy to provide first-in-class medicines. PDD uses empirical, target-agnostic lead generation to identify pharmacologically active molecules and novel therapeutics which work through unprecedented drug mechanisms. The economic and scientific value of PDD is exemplified through game-changing medicines for hepatitis C virus, spinal muscular atrophy, and cystic fibrosis. In this short review, recent advances are noted for the implementation and de-risking of PDD (for compound library selection, biomarker development, mechanism identification, and safety studies) and the potential for artificial intelligence. A significant barrier in the decision to implement PDD is balancing the potential impact of a novel mechanism of drug action with an under-defined scientific path forward, with the desire to provide infrastructure and metrics to optimize return on investment, which a known mechanism provides. A means to address this knowledge gap in the future is to empower precompetitive research utilizing the empirical concepts of PDD to identify new mechanisms and pharmacologically active compounds.

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Screening for Biologically Active Natural Products from Endophytic Fungi

KAGAKU TO SEIBUTSU ◽

10.1271/kagakutoseibutsu.47.390 ◽

2009 ◽

Vol 47 (6) ◽

pp. 390-396

Author(s):

Yoshihito SHIONO ◽

Ken-ichi KIMURA

Keyword(s):

Natural Products ◽

Endophytic Fungi ◽

Biologically Active ◽

Active Natural

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Antiviral Drug Discovery Strategy Using Combinatorial Libraries of Structurally Constrained Peptides

Journal of Virology ◽

10.1128/jvi.78.14.7410-7417.2004 ◽

2004 ◽

Vol 78 (14) ◽

pp. 7410-7417 ◽

Cited By ~ 33

Author(s):

Eléonore Real ◽

Jean-Christophe Rain ◽

Véronique Battaglia ◽

Corinne Jallet ◽

Pierre Perrin ◽

...

Keyword(s):

Drug Discovery ◽

Antiviral Activity ◽

Rabies Virus ◽

Mammalian Cells ◽

Combinatorial Libraries ◽

Biologically Active ◽

Physical Analysis ◽

Constrained Peptides ◽

Pharmacologically Active ◽

Selection Of

ABSTRACT We have developed a new strategy for antiviral peptide discovery by using lyssaviruses (rabies virus and rabies-related viruses) as models. Based on the mimicry of natural bioactive peptides, two genetically encoded combinatorial peptide libraries composed of intrinsically constrained peptides (coactamers) were designed. Proteomic knowledge concerning the functional network of interactions in the lyssavirus transcription-replication complex highlights the phosphoprotein (P) as a prime target for inhibitors of viral replication. We present an integrated, sequential drug discovery process for selection of peptides with antiviral activity directed against the P. Our approach combines (i) an exhaustive two-hybrid selection of peptides binding two phylogenetically divergent lyssavirus P's, (ii) a functional analysis of protein interaction inhibition in a viral reverse genetic assay, coupled with a physical analysis of viral nucleoprotein-P complex by protein chip mass spectrometry, and (iii) an assay for inhibition of lyssavirus infection in mammalian cells. The validity of this strategy was demonstrated by the identification of four peptides exhibiting an efficient antiviral activity. Our work highlights the importance of P as a target in anti-rabies virus drug discovery. Furthermore, the screening strategy and the coactamer libraries presented in this report could be considered, respectively, a general target validation strategy and a potential source of biologically active peptides which could also help to design pharmacologically active peptide-mimicking molecules. The strategy described here is easily applicable to other pathogens.

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Isolation, diversity, and antimicrobial activity of fungal endophytes from Rohdea chinensis (Baker) N.Tanaka (synonym Tupistra chinensis Baker) of Qinling Mountains, China

PeerJ ◽

10.7717/peerj.9342 ◽

2020 ◽

Vol 8 ◽

pp. e9342

Author(s):

Chao An ◽

Saijian Ma ◽

Xinwei Shi ◽

Wenjiao Xue ◽

Chen Liu ◽

...

Keyword(s):

Antimicrobial Activity ◽

Liquid Chromatography ◽

Secondary Metabolites ◽

Endophytic Fungi ◽

High Performance ◽

Fungal Endophytes ◽

Folk Medicine ◽

Antimicrobial Activities ◽

Biologically Active ◽

Qinling Mountains

Endophytic fungi have been emerged as fruitful resources for producing structurally fascinating and biologically active secondary metabolites. However, endophytic fungi from medicinal plants of Qinling Mountains–the most important natural climatic boundary between the subtropical and warm temperate zones of China with an astonishingly high level of biodiversity–have rarely been explored as potential sources of novel fungal species and active secondary metabolites. In this study, a total of 371 fungal colonies were successfully isolated from 510 tissue segments of the medicinal Tupistra chinensis Baker collected from Qinling Mountains, China. Roots of T. chinensis Baker are used as a folk medicine to ameliorate pharyngitis and treat rheumatic diseases. A total of 100 representative morphotype strains were identified according to ITS rDNA sequence analyses and were grouped into three phyla (Ascomycota, Basidiomycota, Mucoromycota), seven classes (Dothideomycetes, Sordariomycetes, Eurotiomycetes, Microbotryomycetes, Agaricomycetes, Leotiomycetes, Mortierellomycetes), and at least 35 genera. The genera of Collectotrichum (IF, 29.92%), Fusarium (IF, 8.36%), Aspergillus (IF, 8.09%), and Dactylonectria (IF, 5.39%) were most frequently isolated from the tissues of T. chinensis Baker. The Species Richness Index (S, 65) and the Shannon-Wiener Index (H′, 3.7914) indicated that T. chinensis Baker harbored abundant fungal resources. Moreover, five isolates were potential new taxa because of low similarity of ITS sequences ranged from 95.09%∼96.61%. Fifteen out of 100 endophytic fungal ethyl acetate extracts exhibited inhibitory activities against at least one pathogenic bacterium or fungus. Two important lead compounds produced by two stains (F8047 and F8075) with high antimicrobial activities were identified using high performance liquid chromatography (HPLC) and ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC–QTOF MS) analyses. In addition, it was noteworthy that the strain F8001, which may be a potential new species, showed antimicrobial activity and should be investigated further. Overall, these results indicated that the endophytic fungi from T. chinensis Baker could be exploited as a novel source of bioactive compounds.

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Electrochemical Behavior of Unusual Dimeric Flavonoids Isolated from Fridericia platyphylla

Journal of the Brazilian Chemical Society ◽

10.21577/0103-5053.20210031 ◽

2021 ◽

Author(s):

Jessyane do Nascimento ◽

Geyse Ribeiro ◽

Silvia Serrano ◽

Roberto de Lima ◽

Auro Tanaka ◽

...

Keyword(s):

Research Group ◽

Electrochemical Behavior ◽

Biologically Active ◽

Oxidation Processes ◽

Potential Value ◽

Oxidation Potentials ◽

Different Types ◽

Pharmacologically Active ◽

First Time ◽

Active Natural

Brazil has the greatest plant diversity on the planet, distributed in different types of biomes. These plants are important sources of biologically active natural products, which are derived from various drugs marketed worldwide. This paper presents an electrochemical study of three unusual dimeric flavonoids, pharmacologically active, isolated and identified for the first time by our research group, in a Brazilian plant (Fridericia platyphylla). The results showed that oxidation processes are favored at higher pH, and mass transport was controlled by diffusion. Brachydins derivatives, Bra-A was oxidized at the lowest potential value (0.48 V vs. Ag/AgCl, KCl(sat)) and Bra-B and Bra-C, presented the highest oxidation potentials (ca. 0.71 and ca. 0.57 V vs. Ag/AgCl, KCl(sat), respectively). This study shows that electrochemistry is one more tool that would help us focus on future bio-pharmacological investigations of these unusual compounds.

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A NOVEL PEPTIDE MODULATOR OF THE HUMAN CHANNEL NAV1.5 FROM LATRODECTUS TREDECIMGUTTATUS SPIDER VENOM

Ambiance in Life International Scientific Journal in Medicine of Southern Caucasus ◽

10.36962/0601202175 ◽

2021 ◽

Vol 06 (01) ◽

pp. 75-75

Author(s):

Shynykul Zhanserik Shynykul Zhanserik

Keyword(s):

Sodium Channels ◽

Biologically Active ◽

Spider Venom ◽

Excitable Cells ◽

Active Peptides ◽

Voltage Gated Sodium Channels ◽

Biologically Active Peptides ◽

Heart Disorders ◽

Pharmacologically Active ◽

Pharmacologically Active Compounds

Spider venom contains a wide repertoire of pharmacologically active compounds, and in the case of some spider species bite, toxins from spider venom can play a fatal role for humans as well as other organisms. Among all the spiders, one could say the bite of Latrodectus tredecimguttatus, known as Black Widow spider, is very dangerous and can even lead to tragic consequences. Especially, voltage-gated sodium channels are responsible for propagating action potentials in excitable cells. NaV1.5 plays a crucial role in the human cardiac muscle, where it enhances the influx of sodium ions via the cell membrane, causing the fast depolarization phase of the cardiac action potential. It is also an important therapeutic target for heart disorders. Various venom-derived peptides have been observed as potential modulators of sodium channels, and these biologically active peptides are an abundant source for pharmacological tools.

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In vitro- exploration of Fungal Endophytes of Egyptian Cynara scolymus L. (artichoke) and Investigation of some their bioactive potentials

Global NEST Journal ◽

10.30955/gnj.002836 ◽

2018 ◽

Keyword(s):

Endophytic Fungi ◽

Biological Activities ◽

Fungal Endophytes ◽

Diversity Indices ◽

Fungal Species ◽

Biologically Active ◽

Bioactive Metabolites ◽

Total Phenolic ◽

Dicaffeoylquinic Acid

Plant-associated microorganisms, especially endophytic fungi, represent an untapped resource for the discovery of biologically active natural products. The objectives of this study were to isolate, identify endophytic fungi, and produce their bioactive metabolites from the leaves of two varieties of Egyptian artichoke namely: French Hyrious and Egyptian Baladi. In addition, assess of their total antioxidant capacity (TAC), total phenolic content (TPC) and total flavonoid content (TFC). The results of this novel study show a total of 35 endophytic fungal species belonging to 14 genera were isolated from both artichoke leaves with gross total counts of colonizing endophytic fungi ranged from 71 to 123 cfu which is matching 78.89% to 136.67% of colonization frequency. All taxa recovered were assigned to Ascomycetes. In addition, there is high species richness and diversity indices of endophytic filamentous fungi in the leaves Baladi Artichoke as compared to its French rival.  Alternaria alternata were found to be the most frequently isolated dominant species. The TAC, TPC and TFC of the fungal cultures ranged from 163 to 681 mgAAE/gDW, 10.38 to 40.30 mgGAE/ gDW, and 13.92 to 173.55 mgQE/gDW, respectively. Furthermore, LC-ESI-MS/MS conﬁrmed the presence of 1,3-dicaffeoylquinic acid and 1,5-dicaffeoylquinic acid in the methanolic extract of A. alternata. Hence, this novel study suggested that the metabolites produced by endophytic fungi associated with Egyptian artichoke could be explored as an economic and potential natural resources with diverse pharmaceutical and biological activities.

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