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Research on Bioactive metabolites from endophytic fungi


Nature of Bioactive metabolites and endophytic fungi

         Bioactive compounds are natural compounds produced by living organisms. They possess pharmacological or biological activities that may be useful in medicine, agriculture and other applications. These bioactive compounds are mostly secondary metabolites which are produced not for growth of the producers as those of the primary metabolites but for other purposes such as cell differentiation and antimicrobial properties.

Structure of paclitaxel (Taxol)

Structure of paclitaxel (Taxol), a natural product obtain from Yew tree



         Endophytes are microbes that live symbiotically inside plant tissues at the intercellular space. Most of the endophytes are fungi and bacteria. The symbiotic interactions between endophytic fungi and their hosts offer benefit to both of them. However, when the interaction is imbalance the fungi may cause certain diseases to the host plants. Endophytes are not only interesting types of microbes but they are also new sources of microbes and bioactive compound producers waiting to be discovered.

Structure of paclitaxel (Taxol)

Microscopic picture of tall fescue leaf sheath cell with endophyte mycelium

Significance of bioactive metabolites and endophytic fungi

         Choices of drugs for treating fungal infections are not that many due to both the fact that increasing emergence of drug resistance pathogens and lesser chance of discovering new drugs with less side effects. The latter was due to the similar nature of fungal and human cells. Using chemical drugs or synthetic drugs for treatment may have some side effects to the patients even though the drugs were targeted to act at the fungal cells and not at the human cells but unexpected outcome from the drugs' side effects were often confronted. A good new drug should have fewer side effects but still retain good antifungal activities toward the target pathogens. At present, scientists are trying harder and harder to develop new versions of synthetic drugs which have the desired properties with less side effects but an alternative approach is opened, that is, to look for new antimicrobial drugs such as the bioactive antifungal compounds from new natural sources such as from endophytic fungi.

         Examples of natural products with antimicrobial activities obtained from some endophytic fungi.

Antifungal compound

Structure of Cryptocandin

Structure of Cryptocandin


Natural product: Cryptocandin
Endophytic fungus: Cryptosporiopsis cf . querina
Host plant: Tripterigeum wifordii
Biological activity: Antifungal ( C.albicans )
Reference: Strobel G. Cryptocandin, a potent antimycotic from the endophytic fungus Cryptosporiopsis cf. querina . Microbiology (1999), 145, 1919-1926.


Antiviral compound

Cytonic acid A and B

Cytonic acid A                                           Cytonic acid B


Natural product: Cytonic acid A and B
Endophytic fungus: Cytonaema sp.
Host plant: Quercus sp.
Biological activity: Antiviral (Human cytomegalovirus (hCMV))
Reference: Bingying Guo. Cytonic A and B: Novel Tridepside Inhibitors of hCMV Protease from the Endophytic Fungus Cytonaema Species. J. Nat. Prod. 2000, 63, 602-604.

Antiviral Agent

Taxol

Taxol


Natural product: Taxol
Endophytic fungus: Taxomyces andreanae
Host plant: Taxus brevifolia
Biological activity: Anticancer
Reference: Suffness, M., Ed. Taxol: Science and Applications ; CRC Press: Boca Raton , Fl, 1995.


Our present research activities on Bioactive metabolites and endophytic fungi



1. Optimization of zofimarin production by an endophytic fungus ACRA L38

Aquilaria crassna or Eagle wood as its common name is a standing timber of Southeast Asia and Australia . It is recognized as an aroma plant because it pleasant aroma given from its essential oils. The oils are useful in aroma treatment making people feel fresh. Sientific studies show that the trees harbour a number of endophytic fungi which can be isolated from various parts of the plants. The part most often found harbouring the endophytes is the leaf. Of those, one endophytic fungus was isolated from a leaf of the tree and was named ACRA L38. The fungus was found to produce zofimarin that possessed activity and had chemical structure similar to that of sordarin, a secondary metabolite produced by Sodaria aregenosa. Since very little is known about zofimarin, various studies to discover the properties of zofimarin use a similar approach previously done with sordarin.

Aquilaria crassna leaf
Aquilaria crassna leaf

Endophytic fungus ACRA L38 on PDA agar culture plate
Endophytic fungus ACRA L38 on PDA agar culture plate

 

         Sordarin is a diterpene glycoside produced by Sordaria areneosa . It was discovered in 1971 in the fermentation broth of Sordaria areneosa culture. Sordarin inhibits translation process at the translocation step.

Cytonic acid A and B

            Sordarin                      Zofimarin (Sordarin derivative)


        
When sordarin binds to eEF-2, it causes changes in conformation of eEF2 which becomes nonfunctional. Therefore, the translocation comes to a stop and consequently causing no protein synthesis and finally leads to cell death. Derivatives of sordarin have different molecules joined to the pyran ring, making some of them more active than sordarin. Zofimarin is also a sordarin derivative that has an acyl group attached to the pyran ring. It is more active than sordarin because the acyl group helps in binding to fungal eEF2 and making the complex stable.

Translocation step of protein synthesis and the action of sordarin

Translocation step of protein synthesis and the action of sordarin

         However, the antibiotic yield was so low that it required optimization study as the first approach. The approach includes physiological studies of the fungus and the effects of pH, temperature, aeration and variation of inoculum sizes on growth and antibiotic yield. The study will elucidate the optimum growth condition and the optimum medium which will give high yield of zofimarin and to understand the importance of medium components including their interactions.

         Objectives of the study
         1. To optimize temperature, pH and aeration (agitation rate) for zofimarin production.
         2. To study the combination effects of carbon sources and their concentrations and the effects of C/N ratios.
         3. To perform orthogonal array experiment to identify the importance of certain media components especially the carbon and nitrogen sources in order to find the best medium formula which gives the highest yield of zofimarin.

 

2. Improvement of mycoepoxydiene production by endophytic fungus Phomopsis sp. Hant25 isolated from Hydnocarpus anthelminthicus

        
Objectives of the study
         1. To improve fermentation method for mycoepoxydiene production by endophytic fungus Phomopsis sp. Hant25 isolated from Hydnocarpus anthelminthicus .
         2. To determine the amount of mycoepoxydiene in culture broth by using High Performance Liquid Chromatography (HPLC)

         In 1999, Ping Cai et al. isolated a novel epoxycyclooctadiene, mycoepoxydiene, from a fungus designated as OS-F66617 which was collected from a twig litter of the deadwood in Brazil . The compound was later shown to exhibit cytotoxicity toward human tumor cells in vitro by Takao et al. In Thailand , mycoepoxydiene has been isolated from an endophytic fungus, Phomopsis sp. Hant25, which was isolated from a twig of Hydnocarpus anthelminthicus , a Thai medicinal plant commonly used for the treatment of leprosy and some kinds of dermatitis, cancer, and tuberculosis. Moreover, Prachya et al. reported that mycoepoxydiene showed cytotoxicity against HepG2, A549, HCC-S102, HuCCA-1, KB, HeLa, MDA-MB231, T47D, HL-60, and P388 cell lines with IC50 values between 0.27 to 2.80 ?g/ml. Because of its interesting biological activities further studies regarding its mechanism of action should be performed. The study would require production of the compound in certain quantity. Preliminary studies employing conventional liquid fermentation both shaking and/or stationary conditions were used for the production of mycoepoxydiene but only low yield of the compound was obtained. Alternative fermentation methods to improve the yield of this bioactive metabolite by the endophytic fungusm Phomopsis sp. Hant25, will be studied.

Our present team work researchers on Bioactive metabolites and endophytic fungi

MIM Laboratory : Students & Members
Dr.Vithaya Meevootisom
Vithaya Meevootisom, Ph.D.
Professor of Microbiology


Thailand Toray Science and Technology Award, 2003
Recipient of Ajinomoto Lecture Award, 1996
Recipient of Mahidol University Award for Excellence in Research, 1988

E-mail: scvmv@mahidol.ac.th

[Research group interests] | [Address] | [Publications]
[Research on phytase and non-starch polysaccharide hydrolase enzymes]
[Research on D-phenylglycine aminotransferase and related enzymes]
[Research on Penicillin acylase enzyme]
[Research on Bioactive metabolites from endophytic fungi]

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Dr.Suthep Wiyakrutta

Nongluksna Sriubolmas, Ph.D.

Associate Professor of Chulalongkorn University (A collaborator)



[Research on Bioactive metabolites from endophytic fungi]

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Dr.Suthep Wiyakrutta

Suthep Wiyakrutta, Ph.D.

Assistant Professor


NRCT Excellent Thesis Award, 1999

E-mail: scsvy@mahidol.ac.th

[Research group interests] | [Address] | [Publications]
[Research on phytase and non-starch polysaccharide hydrolase enzymes]
[Research on D-phenylglycine aminotransferase and related enzymes]
[Research on Penicillin acylase enzyme]
[Research on Bioactive metabolites from endophytic fungi]

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Duangnate Isarangkul Na Ayudhaya
Jirapan Chaichanan

Jirapan Chaichanan

Position:
M.Sc. student

[Research on Bioactive metabolites from endophytic fungi]


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Narukjaporn Thammajaruk

Narukjaporn Thammajaruk

Position:
M.Sc. student

[Research on Bioactive metabolites from endophytic fungi]


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Contact us at:

         Room B600 and B601, 6th Floor, B Building
         Department of Microbiology, Faculty of Science, Mahidol University
         272 Rama VI Road, Bangkok 10400, THAILAND.

         Tel: (662) 0-2201-5536
         Fax: (662) 0-2644-5411
         More information please visit: http://www.sc.mahidol.ac.th/scmi/vmsw.htm

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Address


         >> Department of Microbiology, Faculty of Science, Mahidol University, Rama 6 road, Payatai, Bangkok 10400, Thailand

         Lab Room No:
         >> B600, Tel: (662) 0-2201-5536
         >> B601, Tel: (662) 0-2201-5535

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Representative publications (2003 - present)


Rojanarata T*, Opanasopit P, Ngawhirunpat T, Saehuan C, Wiyakrutta S , Meevootisom V . A simple, sensitive and
         green bienzymatic UV-spectrophotometric assay of amoxicillin formulations. Enzyme Microbial Technol
         2010 Mar;46(3-4):292-296.

Laowanapiban P, Kapustina M, Vonrhein C, Delarue M, Koehl P, Carter CW Jr. Independent saturation of three TrpRS
        subsites generates a partially assembled state similar to those observed in molecular simulations.
         Proc Natl Acad Sci U S A. 2009 Jan 27:17901795

Ingavat N, Dobereiner J, Wiyakrutta S, Mahidol C, Ruchirawat S, Kittakoop P. Aspergillusol A, an alpha-Glucosidase
        Inhibitor from the Marine-Derived Fungus Aspergillus aculeatus. J. Nat. Prod. 2009, 72, 20492052.

Laiwattanapaisal W*, Yakovleva J, Bengtsson M, Laurell T, Wiyakrutta S, Meevootisom V, Chailapakul O, Emn?us J.
        On-chip microfluidic systems for determination of L-glutamate based on enzymatic recycling of substrate.
        
Biomicrofluidics 2009 Jan-Mar;3(1):014104.

Chomcheon P, Wiyakrutta S, Sriubolmas N, Ngamrojanavanich N, Kengtong S, Mahidol C, Ruchirawat S, Kittakoop P.
        Aromatase inhibitory, radical scavenging, and antioxidant activities of depsidones and diaryl ethers from the
        endophytic fungus Corynespora cassiicola L36. Phytochemistry. 2009 Feb;70:407-413.

Chomcheon P, Wiyakrutta S, Sriubolmas N, Ngamrojanavanich N, Mahidol C, Ruchirawat S, Kittakoop P. Metabolites from
        the endophytic mitosporic Dothideomycete sp. LRUB20. Phytochemistry. 2009 Jan;70 (121-127)

Sappapan R, Sommit D, Ngamrojanavanich N, Pengpreecha S, Wiyakrutta S, Sriubolmas N, et al. 11-Hydroxymonocerin
        from the plant endophytic fungus Exserohilum rostratum. J Nat Prod. 2008 Sep;71(9):1657-9.

Kasettrathat C, Ngamrojanavanich N, Wiyakrutta S, Mahidol C, Ruchirawat S, Kittakoop P. Cytotoxic and antiplasmodial
        substances from marine-derived fungi, Nodulisporium sp. and CRI247-01. Phytochemistry.
        2008
October;69(14):2621-6.

Boonman N, Wiyakrutta S, Sriubolmas N, Dharmkrong-at Chusattayanond A. Acanthamoebicidal activity of Fusarium sp.
        Tlau3, an endophytic fungus from Thunbergia laurifolia Lindl. Parasitology research. 2008 Oct;103(5):1083-90.

Chinworrungsee M, Wiyakrutta S, Sriubolmas N, Chuailua P, Suksamrarn A. Cytotoxic activities of trichothecenes isolated
        from an endophytic fungus belonging to order hypocreales. Archives of pharmacal research. 2008 May;31(5):611-6.

Prachyawarakorn V, Mahidol C, Sureram S, Sangpetsiripan S, Wiyakrutta S, Ruchirawat S, et al. Diketopiperazines and
        phthalides from a marine derived fungus of the order pleosporales. Planta Med. 2008 Jan;74(1):69-72.

Saehuan C, Rojanarata T, Wiyakrutta S, McLeish MJ, Meevootisom V. Isolation and characterization of
        a benzoylformate decarboxylase and a NAD+/NADP+-dependent benzaldehyde dehydrogenase involved in D-
        phenylglycine metabolism in Pseudomonas stutzeri ST-201. Biochim Biophys Acta. 2007 Nov;1770(11):1585-92.

Prachya S, Wiyakrutta S, Sriubolmas N, Ngamrojanavanich N, Mahidol C, Ruchirawat S, et al. Cytotoxic mycoepoxydiene
        derivatives from an endophytic fungus Phomopsis sp. isolated from Hydnocarpus anthelminthicus. Planta Med.
        2007
Oct;73(13):1418-20.

Chomcheon P, Sriubolmas N, Wiyakrutta S, Ngamrojanavanich N, Chaichit N, Mahidol C, et al. Cyclopentenones, scaffolds         for organic syntheses produced by the endophytic fungus mitosporic dothideomycete sp. LRUB20. J Nat Prod.
        2006
Sep;69(9):1351-3.

Chomcheon P, Wiyakrutta S, Sriubolmas N, Ngamrojanavanich N, Isarangkul D, Kittakoop P*. 3-Nitropropionic acid
        (3-NPA), a potent antimycobacterial agent from endophytic fungi: Is 3-NPA in some plants produced by endophytes?         J Nat Prod July 2005;68(7):1103-5.

Wiyakrutta S, Sriubolmas N*, Panphut W, Thonggon N, Danwiset-kanjana, Ruangrungsi N, Meevootisom V.
        Endophytic fungi with anti-microbial, anti-cancer and anti-malarial activities isolated from Thai medicinal plants.
        World J Micro Biot Jan 2004;20(3):265-72.

Wang X, Upatham S, Panbangred W, Isarangkul D, Summpunn P, Wiyakrutta S, Meevootisom V*. Purification,
        characterization, gene cloning ans sequence analysis of a phytase from Klebsiella pneumoniae subsp.
        pneumoniae XY-5. ScienceAsia Dec 2004;30(4):383-390.

Rojanarata T, Isarangkul D, Wiyakrutta S, Meevootisom V, Woodley JM*. Controlled-release biocatalysis for the
        synthesis of D-Phenylglycine. Biocatal Biotransfor May 2004;22(3):195-201.

Khampha W, Yakovleva J, Isarangkul D, Wiyakrutta S, Meevootisom V, Emneus J*. Specific detection of L-glutamate
        in food using flow-injection analysis and enzymatic recycling of substrate. Anal Chim Acta Aug 2004;
        518(1-2):127-135.

Khampha W, Meevootisom V, Wiyakrutta S*. Spectrophotometric enzymatic cycling method using L-glutamate
        dehydrogenase and D-phenylglycine aminotransferase for determination of L-glutamate in foods. Anal Chim Acta Aug
        2004
;520(1-2):133-139.

Kongsaeree P*, Samanchart C, Laowanapiban P, Wiyakrutta S, Meevootisom V. Crystallization and preliminary X-ray
        crystallographic analysis of d-phenylglycine aminotransferase from Pseudomonas stutzeri ST201.
        Acta Crystallogr D Biol Crystallogr 2003;59(Pt 5):953-4.

Kongsaeree P*, Prabpai S, Sriubolmas N, Vongvein C, Wiyakrutta S. Antimalarial dihydroisocoumarins produced by
        Geotrichum sp., an endophytic fungus of Crassocephalum crepidioides. J Nat Prod 2003;66(5):709-11.

Plainkum P, Fuchs SM, Wiyakrutta S, Raines RT*. Creation of a zymogen. Nat Struct Biol 2003;10(2):115-9.

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