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Drug Invention Today ISSN: 0975-7619 Review Article www.ditonline.info

Endophytes: Natural Warehouse of Bioactive Compounds Syed Baker, S. Satish* Herbal Drug Technological Laboratory, Department of Studies in Microbiology, University of Mysore, Manasagangotri, Karnataka, India, Mysore 570 006, exposed to a diverse group of microorganisms, Plant and Endophytes are microorganisms that reside asymptomatically in the tissues of higher plants and reported to be promising microbe encounters can be friendly or hostile source of bioactive compounds. Bioactive compounds discovery is a multidisciplinary endeavor that includes the search for new pharmaceuticals from various sources. Endophytes secrete structurally diversified bioactive compounds as secondary metabolite via fermentation process and can be inexhaustible and sustainable resource. Perusal of studies reported so far envisioned that endophytes forms ware house of biologically active compounds. Modern technologies have opened new avenue on endophytic research for highly sustainable and economically feasible novel natural products which are presumed to push forward the frontiers of drug discovery. The present review has compiled reports of diverse class of valuable secondary metabolites produced by endophytes of pharmaceutical importance. Key words: Endophytes, bioactive compounds, Pharmaceuticals

INTRODUCTION Pharmaceutical biology perceives plants as ‘bio-factories’ of potentially valuable therapeutic compounds. But slow growing rate and harvesting of rare endangered species pose a risk and imbalance in the biodiversity of plants. Therefore, alternative sources are outmost essential since organic synthesis are not yet economically feasible and high cost makes it unavailable to people in the under developed countries of the world. In plants thriving communities of microbes do exist as their co-partner. The diversity of microorganism with which plants co-exist can bring both plague and benefit. However, parasitic and symbiotic associations are merely the two extreme outcomes of a continuum of inter organismal interactions. Remarkably little is understood about plant-microbe interplay that is, at first glance, symptomless. Complex communities of poorly studied plant-associated microbes could insight an untapped reservoir of natural products bearing pharmaceutical potential. The more we understand the mechanism of plants tame, thwart and succumb with microorganisms and vice versa, the more likely we will be able to extract new resources of potentially novel therapeutic agents. As the research on plant-microbe interaction upsurge, chemical diversity bearing pharmaceutical potential reached beyond the plant kingdom and offered an expended view promising to transform glimpses of reductionist research of the past years to snapshots of an exuberant world of systems biology by microbial source which forms a huge diversity in nature and is one of the largest unexplored reservoirs forming a “ware house of natural bioactive compounds on the earth”. Hence this has generated more attention and interest over other source such as plant due to various drawbacks [1]. Interest in the exploration of microbial diversity has been spurred by the fact that microbes are essential for sustainable and development of bioactive compounds. If a microbial source of the drug would be available, it would reduce the price for the drug would then be reduced, since it would conceivably be produced via fermentation [2]. Associations between plants and microorganisms is said to be versatile and is very complex subject, plants are constantly

association. However over the years a great deal of scientific attention has been attributed towards plants as it harbor untold number of microbes known as endophytes and epiphytes. Among which endophytic plethora in habitat a unique niches in host and are known to produce novel bioactive compounds of pharmaceutical importance. Starting with the disambiguation of the very definition of endophytes, it gives account of their impact on their applications. Further, it focuses on the nature of the interactions between endophytes and their plant host. Endophytic microorganisms reside in the living tissues of the host plant and do so in a variety of relationships ranging from symbiotic to pathogenic and are found to be in virtually every plant on earth. Endophytes may contribute to their host plant by producing a plethora of substances that provide protection and ultimately survival value to the plant [3].Recently Rodriguez et al., 2008 has classified endophytes based on their role and site at which it has been isolated from plant material and have reported four classes of endophytes which are listed below. Class 1 endophytes frequently increase plant biomass, confer drought tolerance, and produce chemicals that are toxic to animals and decrease herbivory. Class 2 endophytes may grow in both above- and belowground tissues. These class 2 endophytes have their ability to confer habitat-specific stress tolerance to host. Endophyte-conferred fitness benefits are defined here as habitat-adapted if the benefits are a result of habitat-specific selective pressures such as pH, temperature and salinity; or as non habitat-adapted if the benefits are common among endophytes regardless of habitat. Class 3 endophytes are distinguished on the basis of their occurrence primarily or exclusively in above-ground tissues; horizontal transmission; the formation of highly localized. These class of endophytes include the hyperdiverse endophytic fungi associated with leaves of tropical trees as well as the highly diverse associates of above-ground tissues of nonvascular plants, seedless vascular plants, conifers, and

Corresponding Author: S. Satish, Herbal Drug Technological Laboratory, Department of Studies in Microbiology, University of Mysore, Manasagangotri, Mysore- 570 006, Karnataka, India; e-mail:

Received 15-09-2012; Accepted 06-11-2012 November, 2012

Drug Invention Today, 2012, 4(11), 548-553

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Baker and Satish: Endophytes: Natural Warehouse of Bioactive Compounds

woody and herbaceous angiosperms in biomes In addition to occurring within photosynthetic and herbaceous tissues, Class 3 endophytes are found in flowers and fruits, as well as in asymptomatic wood and inner bark Although there is a plethora of knowledge regarding the ecological role and symbiotic functionality of Class 1 endophytes, and a growing body of knowledge regarding Class 2 and 3 endophytes, little is known about the large group of fungi that constitute the Class 4 endophytes [4-5].

required to suppress bacterial growth. Sterile scissors is used to remove outer tissues from sample and to excise inner tissues. Water agar, potato dextrose agar, yeast extract agar, rose bengal chloramphenicol agar, luria bertani agar, Humic acid vitamin agar are found to be suitable nutrient media for isolation of endophytic fungi, bacteria and actinomycetes respectively. Temperature of about 25-30oC is optimum for their growth [12-13].

These endophytes can mimic the chemistry of their respective host plants and make the almost similar bioactive natural products or derivatives that are more bioactive than those of their respective host. This is exemplified with the case of taxol from yews and also taxol being produced by a series of endophytes from yews as well as other plant sources [6]. The ingress to the human population of new disease-causing agents such as requires the discovery and development of new drugs to combat them. New therapies are needed for treating ancillary infections which are a consequence of a weakened immune system and infections by opportunistic pathogens. Hence need for new and useful compounds to provide assistance and relief in all aspects of the human condition is ever-growing. Drug resistance in bacteria, the appearance of life-threatening viruses, the recurrent problems of diseases in persons with organ transplants, and the tremendous increase in the incidence of fungal infections in the world’s population all underscore our inadequacy to cope with these medical problems [3].Secondary metabolites of various reported endophytes are known to have broad antimicrobial activity which play an important role in ongoing efforts to search for novel secondary metabolites in combating the drug resistant microorganism which can be a major threat in the future coming decades [7]. The interest in endophytes first began when fungal endophytes in grasses were found to produce alkaloids which are toxic to herbivores and later in repelling insects [8]. This provided early indications of the possible bioactivity of endophytes which could be further explored for applications as agricultural bioagents. As bioagents, endophytes are valued not only for their potential in conferring resistance to pests and pathogens but for their beneficial association with the host plant as well, such as enhanced nutrient uptake to improve growth, improved tolerance to stress factors and agrochemical agents. Hence research in this area was expanded drastically [8-11].

ISOLATION OF ENDOPHYTES A number of methods for isolation of endophytes are described in literatures. A convenient and common method accepted by many researchers is to dip the tissues in 70% alcohol for few seconds or in 0.5-3.5% sodium hypochlorite for 1-2 minutes followed by rinses in sterile double distilled water before placing it on a nutrient medium for isolation of endophytic microorganisms. Some Isolates require months or more time in culture before they sporulate. For isolation of fungal endophytes surface sterilization of tissue requires 70% ethanol for 1-3 minutes, 4% of aqueous sodium hypochloride for 3-5 minutes again rinse with 70% ethanol 2-10 seconds and final rinse with double distilled water and drying in laminar air flow. In some cases addition of 50mg/l chloramphenicol

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Fig.1: Representing the criteria for screening the potent endophytes of interest

SCREENING OF BIOACTIVE COMPOUNDS Research on endophytes in the recent decades have expanded resulting in isolation of valuable bioactive compound of pharmaceutical importance has generated interest across the globe for deeper study on their behavior from the unique niches and without host. Endophytes got a new face lift with the discovery of taxol producing fungal endophyte which has taken on an added significance, especially in the expansion and efforts to haunt endophytic plethora as ware house of novel potent bioactive compounds of pharmaceutical importance. Various criteria are responsible for screening and isolation of potent endophytes secreting bioactive compound of pharmaceutical interest which is represented by figure-1 such as type of endophyte interested and type of secondary metabolite to be extracted from it .Similarly environmental factors such as geographical area, type of plant from which an endophyte is isolated and type of targeted biological assay being evaluated [12-13].Bioactive compounds of endophytic origin has demonstrated successful significance by producing the desired product via fermentation route and demonstrated a considerable potential to impact the pharmaceutical arena [15-19]. Some of the reported bioactive compounds produced by endophytes represented the unique structure including alkaloids, benzopyranones, chinones, flavonoids, phenolic acids, quinones, steroids, terpenoids, tetralones, xanthones, and others functional bioactivity compounds. Such bioactive metabolites find varied applications as agrochemicals, antibiotics, immunosuppressant, anti parasitics, antioxidants, anticancer biocontrol agents etc., [9]. Some of the prime bioactive compounds bearing functional metabolites for different bioactivity are discussed below individually.


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Antimicrobial Compounds: The accelerating haunt for new antimicrobial drugs to provide assistance in medical community to combat drug resistance microorganism, the appearance of life-threatening viruses, and the tremendous increase in the incidence of fungal infections in the world’s population [18]. Metabolites bearing antimicrobial activity can be defined as lowmolecular-weight compound that are active at low concentrations against pathogenic microorganisms [19]. Research on endophyte has yielded valuable compounds bearing antimicrobial properties such as antifungal, antibacterial and antiviral agents. So far, reported antimicrobial compounds belong to several structural classes like alkaloids, peptides, steroids, terpenoids, phenols, quinines, and flavonoids [20]. Some of them have been briefly described in the present review. A fungal endophyte isolated from Daphnopsis was known to secrete a potentially new class of antibacterial agent “Guanacastepene” showing activity against methicillinresistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium where as bioactive metabolites, “ethyl 2,4-dihydroxy-5,6-dimethylbenzoate” and “phomopsilactone” isolated from an endophytic fungus Phomopsis cassiae from Cassia spectabilis displayed strong antifungal activity against two phytopathogenic fungi, Cladosporium cladosporioides, and C. sphaerospermum [21]. Although the discovery of endophytic compounds having antiviral activity is in its infancy, but some promising endophyte secreting secondary metabolites have found be bearing anti-HIV properties. An endophytic fungus Pestalotiopsis theae was capable of producing “Pestalotheol C” with anti-HIV properties [22]. Endophytic plethora from oak trees resulted in the isolation of a potentially valuable endophyte from the leaves of Quercus coccifera yielded endophyte secreting “Hinnuliquinone” a potent inhibitor of the HIV-1 protease [23].Secondary metabolites “6isoprenylindole-3-carboxylic acid” with antimicrobial property isolated from endophytic microbes was characterized from endophyte Colletotrichum sp [24]. Pseudomonas viridiflava isolated from Grass secreted Ecomycins B and C exhibited potent antimicrobial activity against various important pathogenic microorganisms [25]. Streptomyces griseus isolated from Kandelia candel secreted pAminoacetophenonic acids exhibited potent antimicrobial activity [26]. Streptomyces sp. isolated with Monstera secreted Coronamycin which displayed broad spectrum antimicrobial activity [27]. Similarly Serratia marcescens associated with Rhyncholacis penicillata is reported to secrete Oocydin A, an antifungal agent [13] extracts from endophytes designated as HAB11R3 a Burkholderia sp, HAB10R12 and HAB21F25 both Aspergillus sp isolated from the root of Garcinia scortechinii, exhibited inhibitory activity against methicillin-resistant Staphylococcus aureus [28].Some of the prime compounds bearing broad spectrum antimicrobial activity have been listed in the table-1. Antioxidant Compound: In Nature, natural antioxidants are commonly found in medicinal plants, vegetables, and fruits. Polysaccharides from plants and microorganisms have been extensively studied and considered as potent natural antioxidants The antioxidant agents are highly effective against damage caused by reactive

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oxygen species (ROSs) and oxygen-derived free radicals [35, 36]. Antioxidant agents have been considered promising agents in therapy for prevention and treatment of ROS-linked diseases as cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer and Parkinson diseases), rheumatoid arthritis, and ageing [37]. However, endophytes are reported to be a potential source of novel antioxidants. Many reports confirm the role of bioactive compounds acting as a potent antioxidant agents, some of the bioactive compounds bearing antioxidant property are “Pestacin” “isopestacin” characterized from the endophytic fungus Pestalotiopsis microspora is believed to have potent antioxidant activity higher than Trolox.“Isopestacin” a derivative displayed antioxidant activity by scavenging both superoxide and hydroxyl free radicals [39-40]. Table 1: Some of the reported antimicrobial agents isolated from endophytes [29-34]. Antimicrobial agent 3-O-methylalaternin and “altersolanol A “Phomoenamide” “Phomodione” “Ambuic acid” Munumbicin A, B, C” and “D Cryptocandin

Endophytes Ampelomyces sp

Plant host Urospermum picroides

Phomopsis sp. PSUD15 Phoma species Pestalotiopsis microspora Streptomyces NRRL 30562 Cryptosporiopsis

Garcinia dulcis (Roxb.) Kurz. Saurauia scaberrinae Torreya taxifolia Kennedia nigriscans Cryptosporiopsis cf quercina

The bacterium endophyte Paenibacillus polymyxa produced “exopolysaccharides (EPS)” that demonstrated a potent scavenging activities on superoxide and hydroxyl radicals [41]. “Graphislactone A”, isolated from the endophytic fungus Cephalosporium sp. displays an effective agent having free radical-scavenging and antioxidant activities [42]. Anticancer compound According to the WHO, 80% of the world’s population primarily those of developing countries rely on plant-derived medicines for the health care [43]. Natural products and their derivatives represent more than 50% of all the drugs in clinical use of the world. Higher plants contribute not less than 25% of the total. Almost 60% of drugs approved for cancer treatment are of natural origin. Fruits and vegetables are the principal sources of vitamins C, B, E, carotenoids, and fibers, and these contribute to the apparent cancer-protective effects of the foods. Whereas slow growth rate and extinction of endangered species make pose a risk hence microbial route of bioactive compounds especially against cancer has upsurge in recent years with the invention of taxol. Taxol and some of its derivatives represent the first major group of anticancer agents that are produced by endophytes. Taxol, a highly functionalized diterpenoid, is found in each of the world’s yew (Taxus) species, but was originally isolated from Taxus brevifolia. The original target diseases for this compound were ovarian and breast cancers, but now it is used to treat a number of other human tissue-proliferating diseases as well. The presence of taxol in yew species prompted the study of their endophytes. This compound interferes with the multiplication of cancer cells, reducing or interrupting their growth and spreading. FDA (Food and Drug Administration) has approved Taxol for the treatment of advanced breast


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cancer, lung cancer, and refractory ovarian [44]. Paclitaxel (taxol), as a well-known and highly functionalized tetracyclic diterpenoid bioactive compound found originally from the bark of Taxus brevifolia in 1971 [45]. Its primary mechanism of action is related to the ability to stabilize the microtubules and to disrupt their dynamic equilibrium [46]. Up to now, the major supply of paclitaxel has been from the wild Taxus plants. However, it is found in extremely low amounts in various parts such as the needles, barks and roots of Taxus species. In order to satisfy the growing demand of market and make it more widely available, the alternative resource and potential strategy should be developed. In the last 40 years, many efficient approaches such as field cultivation, plant cell and tissue culture, chemical synthesize for paclitaxel production have been developed, and much progress has been achieved [47]. However, it is not realistic for producing paclitaxel with these measures as the problems of time consuming, lower yield and non economic. Fortunately, a paclitaxel producing endophytic fungus Taxomyces andreanae was successfully discovered from the Pacific yew (Taxus brevifolia) in 1993 [48]. Table 2: Some of the reported antitumor agents isolated from endophytes[52-63]. Podophyllotoxin Cytochalasins Torreyanic acid Cytoskyrins phomoxanthones A” and “B” “photinides A-F” “rubrofusarin B”

Aspergillus fumigatus Rhinocladiella sp. Pestalotiopsis microspora Cytospora sp Phomopsis sp. BCC 1323 Pestalotiopsis photiniae Aspergillus niger. IFB-E003

Juniperus communis L. Horstmann Tripterygium wilfordii T. taxifolia Button wood tree Teak Roystonea regia Cyndon dactylon

This tremendous finding firstly showed that the plant endophytic fungi also had the ability to produce paclitaxel, giving us a novel and promising approach to produce this valuable compound. Since then, many scientists have been increasing their interests in studying fungal endophytes as potential candidates for producing paclitaxel. Extensive research in haunt of important anticancer compound resulted in isolating alkaloid “Camptothecin” (C20H16N2O4), a potent antineoplastic agent which was firstly isolated from the wood of Camptotheca acuminata Decaisne (Nyssaceae) in China .The products were obtained from the endophytic fungi Fusarium solani isolated from Camptotheca acuminate [49]. Phenylpropanoids” belong to the largest group of secondary metabolites produced by plants, recent reports showed the production of such compounds by endophytes. The endophytic Penicillium brasilianum, found in root bark of Melia azedarach, were known to secrete this anti cancerous agent at a large scale via fermentation [50]. In other case he aryl tetralin lignans, such as podophyllotoxin, are naturally synthesized by Podophyllumsps., however, alternative sources have been searched to avoid endangered plant. Another study showed a novel fungal endophyte, Trametes hirsute, that produces podophyllotoxin and other related aryl tetralin lignans with potent anticancer and properties were capable to synthesized with use of endophytic microorganism [51].Table-2 represents profound antitumor agents isolated from endophytes. Antidiabetic Agents A non peptidal fungal metabolite (L-783,281) was isolated from an endophytic fungus (Pseudomassaria sp.) collected

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from an African rainforest. This compound acts as an insulin mimetic but, unlike insulin, is not destroyed in the digestive tract and may be given orally. These results may lead to new therapies for diabetes [64].

FUTURE PROSPECTIVE OF ENDOPHYTE RESEARCH FOR AVENUES IN RESEARCH AND DEVELOPMENT Perusal of studies reported envisioned that endophytes forms ware house of diverse biologically active compounds. Whereas the number of compounds extracted and purified from endophytes entering the field trail and clinical trials is said to be scanty. Some of the future requirements for avenues in research and development are listed below: 1. Isolation of endophytes from unique niches: Isolation of endophytes from various biological niches is one of the important parameter but unfortunately this condition, certainly limits the scope and ability to isolate and culture majority of the interesting and new endophytes. Certainly optimization of growth condition at standard laboratory set up is a crucial stage in endophytic research. 2. Screening of bioactive compounds: As the goal is to obtain the widest possible screening for bioactive compounds. During this stage type of bioactivity expected play an important role for example antimicrobial, anticancerous, antioxidant etc. 3. Extraction of bioactive compounds: Most of the bioactive compound is extracted via fermentation process with the help of solvents such as ethyl acetate, methanol, chloroform etc., as independent solvents or as combinations can be used to obtain crude extracts. Crude extract obtained can be evaluated for particular biological activity. 3. Purification: Once bioactivity is confirmed in the crude extract, the next step is to purify it. The next important process is to adopt non-destructive method for purifying the compounds from crude extract .Each fraction obtained is further employed for biological activity and the fraction exhibiting the biological activity is subjected to characterize for determining the nature and type of structure. 4. Pharmacological screening: The next step after purification and structural elucidation is pharmacological screening. Studies such as in vitro and in vivo determining the LD50 of the extracts in experimental animals, with the type of bioactivity such as antiviral (AIDS/anti- HIV), cytotoxic, antiinflammatory, anti-tumor, tumor promoter (protein kinase), analgesic, anti-coagulant , anti-ulcer, anti-cholesterol / antilipemic, wound dressing, anti-parasitic, anti-protozoa are to be conducted. 5. Commercial development of bioactive products: Collaborative programmes which combining industry in the large scale production of bioactive compound along with research and development cooperation plays an important role to develop the purified bioactive compounds into suitable formulations for further use such as field trials etc in order to develop it into a product.

CONCLUSION The chemical diversity bearing pharmaceutical potential thus implied reaches beyond the plant kingdom with other alternative source of structurally unique natural products that


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are mainly accumulated in living organisms. Several of these compounds exhibit pharmacological activities and are helpful for the invention and discovery of bioactive compounds. Modern technologies have opened new avenue endophytic research as natural ‘warehouse’ with very little have been able to tap from this source so far and among the reported bioactive compounds are briefly mentioned in this review. As the highly desirable search for sustainable and economically feasible new source bioactive compounds has tempted various researchers which in deed have drawn attention proclaiming endophytes creating a huge biodiversity as independent bio-factories, with yet unknown novel natural products presumed to push forward the frontiers of drug discovery.

ACKNOWLEDGEMENT

3.

4.

5. 6. 7.

8.

9. 10.

11.

12.

13.

14.

15.

16.

17.

20. 21.

22.

23.

25.

26.

REFERENCES

2.

19.

24.

Authors are pleased to thank University Grant Commission (UGC) for their financial support and Department of Studies in Microbiology, University of Mysore for providing facilities.

1.

18.

Nicolaou KC, Yang Z, Liu JJ, Ueno H, Nantermet PG, Guy RK, Claiborne CF, Renaud J, Couladouros EA, Paulvannin K, Sorensen EJ, Total synthesis of taxol, Nature, 367, 1994,630-634. Bicas JL, Dionısio AP, Pastore GM, Bio-oxidation of terpenes: an approach for the flavor industry, Chemical Reviews, 109, 2009, 45184531. Strobel G, Daisy B, Castillo U, Harper J, Natural products from endophytic microorganisms, Journal of Natural Products, 67, 2004, 257-268. Rodriguez RJ, Henson J, Van Volkenburgh E, Hoy M, Wright L, Beckwith F, Kim Y, Redman RS, Stress tolerance in plants via habitatadapted symbiosis, International Society of Microbial Ecology , 2, 2008, 404-416. Clay K, Fungal endophytes of grasses: a defensive mutualism between plants and fungi. Ecology, 69, 1988, 10-16. Owen NL, Hundley N, Endophytes the chemical synthesizers inside plants, Science Progress, 87, 2004, 79–99. Liu CH, Zou WX, Lu H, Tan RX, Antifungal activity of Artemisia annua endophytes cultures against phytopathogenic fungi, Journal of Biotechnology, 88, 2001, 277-282. Rowan DD, Hunt MB, and Gaynor DL, Peramine a novel insect feeding deterrent from ryegrass infected with the endophyte Acremonium loliae, Journal of the Chemical Society, 142, 1986, 935-936. Bacon CW, White JF, Microbial Endophytes. Marcel Dekker, New York, 2000, 3-29. Ting ASY, Meon S, Kadir J, Radu S, Singh G, Endophytic microorganisms as potential growth promoters of banana, BioControl, 53, 2008, 541-553. Kimmons CA, Gwinn KD, Bernard EC, Nematode reproduction on endophyte-infected and endophyte-free tall fescue, Plant Disease, 74, 1990, 757-761. Strobel G, Daisy B, Bioprospecting for microbial endophytes and their natural products, Microbiology and Molecular Biology Reviews, 67, 2003, 491–502. Verma VC, Gond SK, Kumar A, Kharwar RN, Strobel GA, The endophytic mycoflora of bark, leaf, and stem tissues of Azadirachta indica A. Juss (Neem) from Varanasi (India), Microbial Ecology, 54, 2007, 119-125. Mahmood T, Gergerich RC, Milus EA, West CP, Arcy CJ, Barley yellow dwarf viruses in wheat, endophyte-infected and endophytefree tall fescue, and other hosts in Arkansas, Plant Disease, 77, 1993, 225-228. Lewis GC, Ravel C, Naffaa W, Astier C, Charmet G, Occurrence of Acremonium endophytes in wild populations of Lolium spp. in European countries and a relationship between level of infection and climate in France, Annals of Applied Biology, 130, 1997, 227-238. Findlay JA, Li G, Johnson JA, Bioactive compounds from an endophytic fungus from eastern larch (Larix laricina) needles, Canadian Journal of Chemistry, 75, 1997, 716-719. Strobel GA, Li JY, Sugawara F, Koshino H, Harper J, Hess WM. Oocydin A, a chlorinated macrocyclic lactone with potent anti-

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

oomycete activity from Serratia marcescens, Microbiology, 145, 1999a, 3557-3564. Tan RX, Zou WX, Endophytes: a rich source of functional metabolites, Natural Product Reports, 18, 2001, 448-459. Strobel G, Daisy B, Bioprospecting for microbial endophytes and their natural products, Microbiology and Molecular Biology Reviews, 67, 2003, 491–502. Strobel GA, Endophytes as sources of bioactive products, Microbes and Infection, 5, 2003, 535-544. Gunatilaka AAL, Natural products from plant-associated microorganisms: Distribution, structural diversity, bioactivity and implication of their occurrence, Journal of Natural Products, 69, 2006, 509-526. Strobel GB, Daisy U, Castillo, Harper J, Natural products from endophytic microorganisms, Journal of Natural Products, 67, 2004, 257-268. Guo B, Wang Y, Sun X, Tang K, Bioactive natural products from endophytes: a review, Applied Biochemistry and Microbiology, 44, 2008, 136-142. Yu H, Zhang L, Li L, Recent developments and future prospects of antimicrobial metabolites produced by endophytes, Microbiological Research, 165, 2010, 437-449. Singh MP, Janso JE, Luckman SW, Brady SF, Clardy J, Greenstein M, Maiese, Biological activity of guanacastepene, a novel diterpenoid antibiotic produced by an unidentified fungus CR115, W. M, The Journal of Antibiotics, 53, 2000, 256-261. Li E, Tian R, Liu S, Chen X, Guo L, Che Y, Pestalotheols A-D, bioactive metabolites from the plant endophytic fungus Pestalotiopsis theae, Journal of Natural Products, 2008, 71, 664-668. Singh SB, Ondeyka JG, Tsipouras N, Ruby C, Sardana V, Schulman M, Sanchez M, Pelaez F, Stahlhut MW, Munshi S, Olsen DB, Lingham RB, Hinnuliquinone, a C2-symmetric dimeric non-peptide fungal metabolite inhibitor of HIV-1 protease, Biochemical and Biophysical Research Communication, 324, 2004,108-13. Lu H, Zou WX, Meng JC, Hu J, Tan R X, New bioactive metabolites produced by Colletotrichum sp., an endophytic fungus in Artemisia annua, Plant science, 151, 2000, 67-73. Miller CM, Miller RV, Garton-Kenny D, Redgrave B, Sears J, Condron MM, Teplow DB Strobel GA, Ecomycins unique antimycotics from Pseudomonas viridiflava, Journal of Applied Microbiology, 84,1998, 937944. Guan SH, Sattler I, Lin WH, Guo DA, Grabley S, pAminoacetophenonic acids produced by a mangrove endophyte: Streptomyces griseus subspecies, Journal of Natural Products, 2005, 68, 1198-1200. Strobel GA, Ezra D, Castillo UF, Coronamycins, peptide antibiotics produced by a verticillate Streptomyces sp. (MSU-2110) endophytic on Monstera sp. , Microbiology 150, 2004,785-793. Sukpondma Y, Rukachaisirikul V, Phongpaichit S, Xanthone and sesquiterpene derivatives from the fruits of Garcinia scortechinii, Journal of Natural Products, 68, 2005,1010–1017. Aly AH, Edrada-Ebel R, Wray V, Bioactive metabolites from the endophytic fungus Ampelomyces sp. isolated from the medicinal plant Urospermum picroides, Phytochemistry, 69, 2008,1716-1725. Rukachaisirikul V, Sommart U, Phongpaichit S, Sakayaroj J, Kirtikara K, Metabolites from the endophytic fungus Phomopsis sp. PSU-D15, Phytochemistry, 69,2008, 783-787. Hoffman AM, Mayer S.G, Strobel GA, Purification, identification and activity of phomodione, a furandione from an endophytic Phoma species, Phytochemistry, 69, 2008, 1049-1056. Li JY, Harper JK, Grant DM, Ambuic acid, a highly functionalized cyclohexenone with antifungal activity from Pestalotiopsis spp. and Monochaetia sp, Phytochemistry, 56, 2001, 463-468. Castillo UF, Strobe, GA, Ford EJ, Hess WM, Porter H, Jensen JB, Albert H, Robison R, Condron MAM, Teplow DB, Stevens D, Yaver D, Munumbicins, wide-spectrum antibiotics produced by Streptomyces NRRL 30562, endophytic on Kennedia nigriscans, Microbiology, 148, 2002, 2675-2685. Strobel GA, Miller RV, Miller C, Condron M, Teplow DB, Hess WM, Cryptocandin, a potent anti mycotic from the endophytic fungus Cryptosporiopsis cf. quercina, Microbiology, 145, 1999, 191-26. Huang WY, Cai YZ, Xing J, Corke H, Sun M, A potential antioxidant resource: endophytic fungi from medicinal plants, Economic Botany, 61, 2007, 14-30. Seifried HE, Anderson DE, Fisher EI, and Milner JA, A review of the interaction among dietary antioxidants and reactive oxygen species, Journal of Nutritional Biochemistry, 18, 2007,567-579. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J, Free radicals and antioxidants in normal physiological functions and

552 November, 2012



42.

43. 44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

human disease, International Journal of Biochemistry and Cell Biology, 39, 2007,44-84. Liu X, Dong M, Chen X, Jiang M, Lv X, Yan G, Antioxidant activity and phenolics of an endophytic Xylaria sp. from Ginkgo biloba, Food Chemistry, 105, 2007, 548–554. Gurib-Fakim A, Medicinal plants: traditions of yesterday and drugs of tomorrow, Molecular Aspects of Medicine, 27, 2006, 1-93. Harper JK, Arif AM, Ford EJ, Pestacin: a 1, 3- dihydro isobenzofuran from Pestalotiopsis microspora possessing antioxidant and antimycotic activities, Tetrahedron, 59, 2003, 2471-2476. Strobel G, Ford E, Worapong J, Isopestacin, an isobenzofuranone from Pestalotiopsis microspora, possessing antifungal and antioxidant activities, Phytochemistry, 60, 2002, 179-183. Liu J, Luo J, Ye H, Sun Y, Lu Z, Zeng X, Production, characterization and antioxidant activities in vitro of exopolysaccharides from endophytic bacterium Paenibacillus polymyxa EJS-3, Carbohydrate Polymers, 78, 2009, 275–281. Song YC, Huang WY, Sun C, Wang FW, Tan R.X, Characterization of graphislactone A as the antioxidant and free radical-scavenging substance from the culture of Cephalosporium sp. IFB-E001, an endophytic fungus in Trachelospermum jasminoides, Biological and Pharmaceutical Bulletin, 28, 2005,506–509. Cremasco MA, Hritzko BJ, Linda Wang NH, Experimental purification of paclitaxel from a complex mixture of taxanes using a simulated moving bed, Brazilian Journal of Chemical Engineering, 26, 2009, 207218. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail A, Plant antitumor agents. VI. The isolation and structure of Taxol, a novel anti leukemic and antitumor agent from Taxus brevifolia, Journal of the American Chemical Society, 93, 1971, 2325-2327. Wang LG, Liu XM, Kreis W, Budman DR, The effect of anti microtubule agents on signal transduction pathways of apoptosis, Cancer Chemotherapy and Pharmacology, 44, 1999, 355-361. Zhou L, Wu J, Development and application of medicinal plant tissue cultures for production of drugs and herbal medicinal in China, Natural Product Reports, 23, 2006, 789-810. Xu L, Zhou L, Zhao J, Jiang W, Recent studies on the antimicrobial compounds produced by plant endophytic fungi, Natural Product Research and Development, 20.2008 731-740. Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA, Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, Journal of the American Chemical Society, 88, 1966, 38883890.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

Fill TP, Da Silva BF, Rodrigues-Fo E, Biosynthesis of phenylpropanoid amides by an endophytic penicillium brasilianum found in root bark of Melia azedarach, Journal of Microbiology and Biotechnology, 20, 2010, 622-629. Kusari S, Lamshoft M, Spiteller M, Aspergillus fumigatus Fresenius, an endophytic fungus from Juniperus communis L. Horstmann as a novel source of the anticancer pro-drug deoxypodophyllotoxin, Journal of Applied Microbiology, 107, 2009, 1019-1030. Kour A, Shawl AS, Rehman S, Isolation and identification of an endophytic strain ofFusarium oxysporum producing podophyllotoxin from Juniperus recurva, World Journal of Microbiology and Biotechnology, 24, 2008, 1115-1121. Puri SC, Nazir A, Chawla R, The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin lignans, Journal of Biotechnology,122, 2006, 494-510. Wagenaar MM, Corwin J, Strobel G, Clardy J, Three new cytochalasins produced by an endophytic fungus in the genus Rhinocladiella, Journal of Natural Products, 63, 2000, 1692-1695. Lee JC, Strobel GA, Lobkovsky E, Clardy J, Torreyanic acid: a selectively cytotoxic quinone dimer from the endophytic fungus Pestalotiopsis microspora, Journal of Organic Chemistry, 61, 1996, 3232-3233. Brady SF, Singh MP, Janso JE, Clardy J, Cytoskyrins A and B, new BIA active bisanthraquinones isolated from an endophytic fungus, Organic Letters, 2, 2000, 4047-4049. Isaka M, Jaturapat A, Rukseree K, Danwisetkanjana K, Tanticharoen M, Thebtaranonth Y, Phomoxanthones A and B, novel xanthone dimers from the endophytic fungus Phomopsisspecies, Journal of Natural Products, 64, 2001, 1015-1018. Ding G, Zheng Z, Liu S, Zhang H, Guo L, Che Y, Photinides A-F, cytotoxic benzofuranone-derived γ-lactones from the plant endophytic fungus Pestalotiopsis photiniae, Journal of Natural Products, 72, 2009, 942-945. Song YC, Li H, Ye YH, Shan CY, Yang YM, Tan RX, Endophytic naphthopyrone metabolites are co-inhibitors of xanthine oxidase, SW1116 cell and some microbial growths, FEMS Microbiology Letters, 241, 2004, 67-72. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Dez M, Pelaez F, Ruby C, Kendall RL, Mao X, Griffin P, Calaycay J, Zierath JR, Heck JV, Smith RG, Moller DE, . Discovery of small molecule insulin mimetic with antidiabetic activity in mice. Science, 284,1999,974-981.

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Source of support: Nil, Conflict of interest: None Declared

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