Bioactive Compounds from Endophytes and their Potential in Pharmaceutical Effect: A Review
R. Mini Priya
Endophytes are microorganisms that live inside the host plant tissues which have novel metabolites exhibiting a variety of biological activities against different diseases. In fact, a significant number of interesting natural bioactive compounds have been reported in the last years. The microbial biotransformation process is a novel alternative method to obtain bioactive compounds. In this review, some aspects in the phytochemistry of endophytes producing Phytochemicals and its pharmaceutical effects are discussed.
Received: November 01, 2010;
Accepted: December 21, 2010;
Published: April 29, 2011
Many complementary and alternative medicines have enjoyed increased popularity
in recent decades (Joseph and Priya, 2011). Drugs derived
from natural sources play a significant role in the prevention and treatment
of human diseases. About 61% of new drugs developed between 1981 and 2002 were
based on natural products and they have been very successful especially in the
areas of infectious disease and cancer (Cragg and Newman,
2005). More than 90% of the terms recorded in Indian medical literature
are derived from plant sources (Joseph and Priya, 2010).
For the fast two years, there has been an increasing interest in the investigation
of different novel natural bioactive products from plants (Joseph
et al., 2010). Recent trends, however, show that the discovery rate
of active novel chemical entities is declining (Lam, 2007).
Therefore, there is a need to bio-prospect new sources and if possible from
less explored regions and habitats to maximize the discovery of novel bioactive
Endophytes are microorganisms that include bacteria and fungi living within
plant tissues without causing any immediate overt negative effects have been
found in every plant species examined to date and recognized as the potential
sources of novel natural products for exploitation in medicine, agriculture
and industry with more bioactive natural products isolated from the microorganisms
(Bacon and White, 2000; Strobel and
Daisy, 2003; Kumar and Sagar, 2007). Endophytes
are ubiquitous with rich biodiversity, which have been found in every plant
species examined to date. It is noteworthy that, of the nearly 3, 00,000 plant
species that exist on the earth, each individual plant is the host to one or
more endophytes (Strobel and Daisy, 2003). In this view
of the special colonization in certain hosts, it is estimated that there may
be as many as 1 million different endophyte species. However, only a handful
of them have been described (Andrew and Hirano, 1991),
which means the opportunity to find new and targeting natural products from
interesting endophytic microorganisms among myriads of plants in different niches
and ecosystems is great. Some of the endophytes are the chemical synthesizers
in inside the plants (Owen and Hundley, 2004).
Many of them are capable of synthesizing bioactive compounds that can be used
by plants for defense against human pathogens and some of these compounds have
been proven useful for novel drug discovery. Recent studies have reported hundreds
of natural products including substance of alkaloids, terpenoids, flavonoids,
steroids, etc. from endophytes. Up to now, most of the natural products from
endophytes are antibiotics, anticancer agents, biological control agents and
other bioactive compounds by their different functional roles. Thus far, they
have not been widely explored for therapeutic properties. A single endophyte
may be able to produce not one but several bioactive metabolites. As a result,
the role of endophytes in the production of novel structures for exploitation
in medicine is receiving increased attention (Wang et
al., 2000; Ezra et al., 2004a;
A small amount of endophytes have been studied, recently, several research
groups have been motivated to evaluate and elucidate the potential of these
microorganisms applied on biotechnological processes focusing on the production
of bioactive compounds. The production of bioactive substances by endophytes
is directly related to the independent evolution of these microorganisms, which
may have incorporated genetic information from higher plants, allowing them
to better adapt to plant host and carry out some functions such as protection
from pathogens, insects and grazing animals (Strobel, 2003).
Endophytes are chemical synthesizer inside plants (Owen
and Hundley, 2004), in other words, they play a role as a selection system
for microbes to produce bioactive substances with low toxicity toward higher
organisms (Strobel, 2003). Bioactive natural compounds
produced by endophytes have been promising potential usefulness in safety and
human health concerns, although there is still a significant demand of drug
industry for synthetic products due to economic and time-consuming reasons (Strobel
et al., 2004). Problems related to human health such as the development
of drug resistance in human pathogenic bacteria, fungal infections and life
threatening virus claim for new therapeutic agents for effective treatment of
diseases in human, plants and animals that are currently unmet (Strobel
and Daisy, 2003; Strobel, 2003; Zhang
et al., 2005). Recent review by Cragg and Newman
(2007) presented a list of all approved agents from 1981 to 2006, from which
a significant number of natural drugs are produced by microbes and/or endophytes.
Endophytes provide a broad variety of bioactive secondary metabolites with unique
structure, including alkaloids, benzopyranones, chinones, flavonoids, phenolic
acids, quinones, steroids, terpenoids, tetralones, xanthones and others (Tan
and Zou, 2001). Such bioactive metabolites find wide-ranging application
as agrochemicals, antibiotics, immunosuppressants, antiparasitics, antioxidants
and anticancer agents (Gunatilaka, 2006).
Methods to obtain bioactive compounds include the extraction from a natural
source, the microbial production via fermentation, or microbial transformation.
Extraction from natural sources presents some disadvantages such as dependency
on seasonal, climatic and political features and possible ecological problems
involved with the extraction, thus calling for innovative approaches to obtain
such compounds (Bicas et al., 2009). Hence, biotechnological
techniques by using different microorganisms appear promising alternatives for
establishing an inexhaustible, cost-effective and renewable resource of high-value
bioactive products and aroma compounds. The biotransformation method has a huge
number of applications (Borges et al., 2009),
for instance, it has been extensively employed for the production of volatile
compounds (Bicas et al., 2009; Bicas
et al., 2008; Krings et al., 2006).
These volatile compounds possess not only sensory properties, but other desirable
properties such as antimicrobial (vanillin, essential oil constituents), antifungal
and antiviral (some alkanolides), antioxidant (eugenol, vanillin), somatic fat
reducing (nootkatone), blood pressure regulating (2-[E]-hexenal), anti-inflammatory
properties (1,8-cineole) and others (Berger, 2009).
The intent of this review is to provide insights into the phytochemistry of
endophytes producing phytochemicals, biological effects of endophytes producing
bioactive compounds, the importance of including endophytic microbes for novel
drugs and the microbial biotransformation process as a novel alternative method
to obtain bioactive compounds. This review, however, also describes these compounds
by different functions and pharmaceutical potential for human use.
Tan and Zou (2001) believe the reason why some endophytes
produce certain phytochemicals originally characteristic of the host might be
related to a genetic recombination of the endophyte with the host that occurs
in evolutionary time. This is a concept that was originally proposed as a mechanism
to explain why the endophytic fungus T. andreanae may be producing paclitaxel
(Stierle et al., 1993). Thus, if endophytes can
produce the same rare and important bioactive compounds as their host plants,
this would not only reduce the need to harvest slowgrowing and possibly rare
plants but also preserve the worlds ever diminishing biodiversity. Furthermore,
it is recognized that a microbial source of a valued product may be easier and
more economical to produce, effectively reducing its market price (Strobel
and Daisy, 2003).
All aspects of the biology and interrelatedness of endophytes with their respective
hosts is a vastly under investigated and exciting field. Thus, more background
information on a given plant species and its microorganismal biology would be
exceedingly helpful in directing the search for bioactive products. Currently,
no one is quite certain of the role of endophytes in nature and what appears
to be their relationship to various host plant species. While some endophytic
fungi appear to be ubiquitous (e.g., Fusarium species, Pestalotiopsis
species and Xylaria species), one cannot definitively state that
endophytes are truly host specific or even systemic within plants any more than
one can assume that their associations with plants are chance encounters. Frequently,
many endophytes (biotypes) of the same species are isolated from the same plant
and only one of the endophytes will produce a highly biologically active compound
in culture (Li et al., 1996). A great deal of
uncertainty also exists between what an endophyte produces in culture and what
it may produce in nature. It does seem apparent that the production of certain
bioactive compounds by the endophyte in situ may facilitate the domination of
its biological niche within the plant or even provide protection to the plant
from harmful invading pathogens. This may be especially true if the bioactive
product of the endophyte is unique to it and is not produced by the host. Seemingly,
this would more easily facilitate the study of the role of the endophyte and
its role in the plant. Furthermore, little information exists relative to the
biochemistry and physiology of the interactions of the endophyte with its host
plant. It would seem that many factors changing in the host as related to the
season and age, environment and location may influence the biology of the endophyte.
Indeed, further research at the molecular level must be conducted in the field
to study endophyte interactions and ecology. The ecological awareness of the
role these organisms play in nature will provide the best clues for targeting
particular types of endophytic bioactivity with the greatest potential for bio-prospecting
(Strobel and Daisy, 2003).
BIOPHARMACEUTICAL EFFECTS OF ENDOPHYTES
The following section shows effects of bioactive compounds obtained from endophytic microbes and their potential in the pharmaceutical and agrochemical areas.
Antimicrobial effect: Metabolites bearing antibiotic activity can be
defined as low-molecular-weight organic natural substances made by microorganisms
that are active at low concentrations against other microorganisms (Guo
et al., 2008). Endophytes are believed to carry out a resistance
mechanism to overcome pathogenic invasion by producing secondary metabolites
(Tan and Zou, 2001). So far, studies reported a large
number of antimicrobial compounds isolated from endophytes, belonging to several
structural classes like alkaloids, peptides, steroids, terpenoids, phenols,
quinines and flavonoids (Yu et al., 2010). The
discovery of novel antimicrobial metabolites from endophytes is an important
alternative to overcome the increasing levels of drug resistance by plant and
human pathogens, the insufficient number of effective antibiotics against diverse
bacterial species and few new antimicrobial agents in development, probably
due to relatively unfavorable returns on investment (Yu
et al., 2010; Song, 2008). The antimicrobial
compounds can be used not only as drugs by humankind but also as food preservatives
in the control of food spoilage and food-borne diseases, a serious concern in
the world food chain (Liu et al., 2008).
Many bioactive compounds, including antifungal agents, have been isolated from
the genus Xylaria residing in different plant hosts, such as sordaricin
with antifungal activity against Candida albicans (Pongcharoen
et al., 2008), mellisol and 1,8- dihydroxynaphthol 1-O-a-glucopyranoside
with activity against herpes simplex virus type 1 (Pittayakhajonwut
et al., 2005), multiplolides A and B with activity against Candida
albicans (Boonphong et al., 2001). The
bioactive compound isolated from the culture extracts of the endophytic fungus
Xylaria sp. YX-28 isolated from Ginkgo biloba L. was identified
as 7-amino-4-methylcoumarin (Liu et al., 2008).
The compound presented broad-spectrum inhibitory activity against several food-borne
and food spoilage microorganisms including S. aureus, E. coli, S. typhia,
S. typhimurium, S. enteritidis, A. hydrophila, Yersinia sp., V. anguillarum,
Shigella sp., V. parahaemolyticus, C. albicans, P. expansum and A.
niger, especially to A. hydrophila and was suggested to be used as
natural preservative in food (Liu et al., 2008).
Another strain F0010 of the endophytic fungus Xylaria sp., from Abies
holophylla was characterized as a producer of griseofulvin, a spirobenzofuran
antifungal antibiotic agent used for the treatment of human and veterinary animals
mycotic diseases (Park et al., 2005). They evaluated
and reported high antifungal activity in vivo and in vitro of
the endophyte-produced griseofulvin against plant pathogenic fungi, controlling
effectively the development of various food crops. Aliphatic compounds, frequently
detected in cultures of endophytes, often show biological activities. Four antifungal
aliphatic compounds were characterized from stromata of E. typhina on
P. pratense (Koshino et al., 1989). Two
novel ester metabolites isolated from an endophyte of the eastern larch presented
antimicrobial activity. One compound was toxic to spruce budworm (Choristoneura
fumiferana Clem.) larvae and the other may serve as potent antibacterial
agent against Vibrio salmonicida, Pseudomonas aeruginosa and Staphylococcus
aureus (Findlay et al., 1997a). Chaetomugilin
A and D with antifungal activities were isolated from an endophytic fungus C.
globosum collected from Ginkgo biloba (Qin et
al., 2009). Cytosporone B and C were isolated from a mangrove endophytic
fungus, Phomopsis sp. They inhibited two fungi C. albicans and
F. oxysporum with the MIC value ranging from 32 to 64 mg Ml -1
(Huang et al., 2008).
Chlorinatedmetabolites such as (-) mycorrhizin A, (+)- cryptosporiopsin isolated
from endophytic Pezicula strains were reported as strongly fungicidal
and herbicidal agents and to a lesser extent, as algicidal and antibacterial
agents (Schulz et al., 1995). Similarly, two
other new chlorinated benzophenone derivatives, Pestalachlorides A and B, from
the plantendophytic fungus Pestalotiopsis adusta, proven to display significant
antifungal activity against three plant pathogenic fungi, Fusarium culmorum,
Gibberella zeae and Verticillium albo-atrum (Li
et al., 2008a). The production of Hypericin, a naphthodianthrone
derivative and Emodin believed to be the main precursor of hypericin by the
endophytic fungus isolated from an Indian medicinal plant was reported. Both
compounds demonstrated antimicrobial activity against several bacteria and fungi
including Staphylococcus aureus sp., aureus, Klebsiella pneumoniae
sp., ozaenae, Pseudomonas aeruginosa, Salmonella enterica sp.,
Enteric and Escherichia coli and fungal organisms Aspergillus
niger and Candida albicans (Kusari et al.,
An endophytic Streptomyces sp., from a fern-leaved grevillea (Grevillea
pteridifolia) in Australia was described as a promising producer of novel
antibiotics, kakadumycin A and echinomycin. Kakadumycin A is structurally related
to echinomycin, a quinoxaline antibiotic and presents better bioactivity than
echinomycin especially against Grampositive bacteria and impressive activity
against the malarial parasite Plasmodium falciparum (Castillo
et al., 2003). Another novel endophytic Streptomyces SUK 06 from
Thottea grandiflora in Malaysia was reported bioactive secondary metabolites
with ethyl acetate have killing activity against Bacillus subtilis, Pseudomonas
aeruginosa, Bacillus cereus, Pleisiomonas shigelloides and MRSA. Nevertheless,
there were some antifungal activity measured against Fusarium solani,
Aspergillus fumigatus, Pythium ultimum, Phytophthora erythroseptica
and Geothrichum candidum (Ghadin et al., 2008).
More than 50% of endophytic fungi strains residing in Quercus variabilis
possessed growth inhibition against at least one pathogenic fungus or bacteria.
Cladosporium sp., displaying the most active antifungal activity, was
investigated and found to produce a secondary metabolite known as brefeldin
A, a lactone with antibiotic activity. Results showed brefeldin A to be more
potent than the positive control in antifungal activity (Wang
et al., 2007).
Coronamycin, a peptide antibiotic produced by an endophytic fungi Streptomyces
sp., isolated from Monstera sp., is active against pythiaceous fungi,
the human fungal pathogen Cryptococcus neoformans and the malarial parasite,
Plasmodium falciparum (Ezra et al., 2004b).
Production of lipopeptide pumilacidin, an antifungal compound, by B.
pumilus isolated from cassava cultivated by Brazilian Amazon Indian tribes
was described for the first time (De Melo et al.,
2009). The compounds 2-hexyl-3-methyl-butanodioic acid and cytochalasin
D were isolated from the endophytic fungus Xylaria sp., Isolated from
Brazilian Cerrado and presented antifungal activity (Cafeu
et al., 2005). Two new bioactive metabolites, ethyl 2, 4-dihydroxy-5,
6-dimethylbenzoate and phomopsilactone were isolated from an endophytic fungus
Phomopsis cassiae from Cassia spectabilis and displayed strong
antifungal activity against two phytopathogenic fungi, Cladosporium cladosporioides
and C. sphaerospermum (Silva et al., 2005).
The polyketide citrinin produced by endophytic fungus Penicillium janthinellum
from fruits of Melia azedarach, presented 100% antibacterial activity
against Leishmania sp. (Marinho et al., 2005).
Among the 12 secondary metabolites produced by the endophytic fungi Aspergillus
fumigatus CY018 isolated from the leaf of Cynodon dactylon, asperfumoid,
fumigaclavine C, fumitremorgin C, physcion and helvolic acid were shown to inhibit
Candida albicans (Liu et al., 2004).
Endophyte Verticillium sp., isolated from roots of wild Rehmannia
glutinosa produced two compounds 2, 6-Dihydroxy-2- methyl-7- (prop-1E-enyl)-1-benzofuran-3(2H)-one,
reported for the first time and ergosterol peroxide with clear inhibition of
the growth of three pathogens including Verticillium sp., (You
et al., 2009).
Another fascinating use of antibiotic products from endophytic fungi is the
inhibition of viruses. Two novel human cytomegalovirus protease inhibitors,
cytonic acids A and B have been isolated from the solid-state fermentation of
the endophytic fungus Cytonaema sp., Their structures as p-tridepside
isomers were elucidated by mass spectrometry and NMR methods (Guo
et al., 2000). An endophytic fungus Pestalotiopsis theae of
an unidentified tree on Jianfeng Mountain, China, was capable of producing Pestalotheol
C with anti-HIV properties (Li et al., 2008b).
It is apparent that the potential for the discovery of compounds, from endophytes,
having antiviral activity is in its infancy. The fact, however, that some compounds
have been found is promising. The main limitation in compound discovery is probably
related to the absence of appropriate antiviral screening systems in most compound
discovery programs (Strobel and Daisy, 2003).
Another interesting aspect of this research, newly described endophytic fungus
Muscodor albus from small limbs of Cinnamomum zeylanicum effectively
inhibits and kills certain other fungi and bacteria by producing a mixture of
volatile compounds (Worapong et al., 2001; Strobel
et al., 2001). This mixture mimicked the antibiotic effects of the
volatile compounds produced by the fungus. It was also used to gain positive
identification of the ingredients of the fungal volatile compounds (Strobel
et al., 2001). Each of the five classes of volatile compounds produced
by the fungus had some inhibitory effect against the test fungi and bacteria,
but none was lethal. The most effective class of inhibitory compounds was the
esters, of which isoamyl acetate was the most biologically active. The ecological
implications and potential practical benefits of the mycofumigation effects
of M. albus are very promising given the fact that soil fumigation utilizing
methyl bromide. This fungus is just as effective in causing inhibition and death
of test microbes in the laboratory as M. albus (Worapong
et al., 2002). In addition, for the first time, a non-muscodor species,
a Gliocladium sp., was discovered to be a volatile antibiotic producer.
Another important aspect of this research is inhibition of plant pathogens
which is relevant in agriculture field. Many endophytic species produce antibiotic
substances (Schulz and Boyle, 2005; Strobel
et al., 2002; Wang et al., 2007).
Liquid extracts from endophyte cultures have been found to inhibit the growth
of several species of plant pathogenic fungi (Liu et
al., 2001; Park et al., 2005; Inacio
et al., 2006; Kim et al., 2007). If such
compounds where produced by endophytes in plants, this could constitute a defense
mechanism against fungal pathogens. Experiments where plant protection against
pathogenic fungi is observed after the inoculation of plants with endophytes,
as well as after the application of endophytic culture filtrates, suggest that
the endophyte may produce an antifungal compound or a substance that induces
plant defense mechanisms in the plant. This is the case with Chaetomium and
Phoma endophytes of wheat, when these fungi were previously inoculated
in plants, reduced severity of foliar disease caused by Puccinia and
Pyrenophora sp., was observed and, the same protective effect was observed
when only endophytic culture filtrates were applied to the plants (Dingle
and McGee, 2003; Istifadah and McGee, 2006). Rajendran
et al. (2008) reported that the management of Basal Stem Rot disease
sixty endophytic, rhizosphere strains was isolated from coconut, other crops
and virgin soils. The strains showed high growth promotion were subjected to
Ganoderma mycelium inhibition study in vitro. The strains EPC5
and EPC8 were showed high growth promotion and strong inhibition to Ganoderma
When a mixture of six species of endophytes frequently isolated from cacao
(Theobroma cacao L.) trees was used to inoculate leaves of endophyte-free
seedlings of this plant species, the severity of a leaf disease caused by a
Phytophthora sp., was significantly reduced in endophyte-inoculated leaves.
A mechanism of induced plant resistance did not seem to be involved, because
differences in disease severity were observed between endophyte-inoculated and
non-inoculated leaves of the same plant. In this case, the protection against
a pathogen could be the result of direct competition among endophytes already
present in leaves and the pathogen (Arnold et al.,
2003). For instance, most tissue available for infection may be already
occupied, or endophytes may produce zones of inhibition restricting the entry
of other fungi.
Endophyte infection may alter plant biochemistry in a way that defense mechanisms
against pathogens are induced. Piriformospora indica Sav. Verma, Aj.
Varma, Rexer, G. Kost and P. Franken are a root endophyte with a wide host range,
including several species of cereals and Arabidopsis. Barley plants inoculated
with this endophyte have shown resistance to a vascular (Fusarium culmorum
(W.G. Sm.) Sacc.) and a leaf pathogen [Blumeria graminis (DC) Speer],
in addition to an increase in yield and salt stress tolerance (Waller
et al., 2005). The protection against the leaf pathogen appears to
be mediated by a mechanism of induced resistance, because in the pathogen-inoculated
plants there is a defense response involving the death of host cells.
Some endophytes may be mycoparasites. Acremonium strictum W. Gams is
an endophyte which has been frequently isolated from Dactylis glomerata L.
and other grasses (Marquez et al., 2007), recently
it has been shown that this fungus is a mycoparasite of Helminthosporium
solani Durieu and Mont., a potato pathogen (Rivera -Varas
et al., 2007). A significant increase in resistance to dollar spot
disease, caused by Sclerotinia homoeocarpa F.T. Benn., has been observed
in Festuca rubra L. cultivars infected by Epichloë festucae Leuchtm.,
Schardl and M.R. Siegel. (Clarke et al., 2006).
Cultivars of several turfgrass species infected by Epichloe and Neotyphodium
endophytes are commercially available at the present time. The efficient
vertical transmission of these endophytes has allowed the production of infected
seed at a commercial scale. Since Neotyphodium and Epichloe infected
cultivars have shown increased resistance to herbivores, plant pathogens and
some conditions of abiotic stress, the use of such symbiotic cultivars can result
in a reduction in the use of insecticides and fungicides in lawns (Brilman,
Antioxidant effect: Many antioxidant compounds possess anti-inflammatory,
antiatherosclerotic, antitumor, antimutagenic, anticarcinogenic, antibacterial,
or antiviral activities in higher or lower level (Owen et
al., 2000; Cozma, 2004; Halliwell,
1994; Mitscher et al., 1996; Sala
et al., 2002). Natural antioxidants are commonly found in medicinal
plants, vegetables and fruits. However, it has been reported that metabolites
from endophytes can be a potential source of novel natural antioxidants. (Liu
et al., 2007) evaluated the antioxidant activity of an endophytic
Xylaria sp., isolated from the medicinal plant Ginkgo biloba.
The results collected indicated that the methanol extract exhibited strong antioxidant
capacity due to the presence of phenolics and flavonoids compounds among 41
identified compounds. Huang and coworkers investigated the antioxidant capacities
of endophytic fungal cultures of medicinal Chinese plants and its correlation
to their total phenolic contents. They suggested that the phenolic content were
the major antioxidant constituents of the endophytes (Huang
et al., 2007). Pestacin and isopestacin, 1, 3-dihydro isobenzofurans,
were obtained from the endophytic fungus Pestalotiopsis microspora isolated
from a plant growing in the Papua New Guinea, Terminalia morobensis (Harper
et al., 2003; Strobel et al., 2002).
Besides antioxidant activity, pestacin and isopestacin also presented antimycotic
and antifungal activities, respectively. Pestacin is believed to have antioxidant
activity 11 times greater than Trolox, a vitamin E derivative, primarily via
cleavage of an unusually reactive C-H bond and to a lesser extent, O-H abstraction
(Harper et al., 2003). Isopestacin possess antioxidant
activity by scavenging both superoxide and hydroxy free radicals in solution,
added to the fact that isopestacin is structurally similar to the flavonoids
(Strobel et al., 2002).
Liu et al. (2009) reported for the first time,
the capacity of endophytic microorganisms to produce polysaccharides with antioxidant.
The bacterium endophyte Paenibacillus polymyxa isolated from the root
tissue of Stemona japonica Miquel, a traditional Chinese medicine, produced
exopolysaccharides (EPS) that demonstrated strong scavenging activities on superoxide
and hydroxyl radicals. Graphislactone A, a phenolic metabolite isolated from
the endophytic fungus Cephalosporium sp., IFB-E001 residing in Trachelospermum
jasminoides, demonstrated to have free radical-scavenging and antioxidant
activities in vitro stronger than the standards, Butylated Hydroxytoluene
(BHT) and ascorbic acid, coassayed in the study (Song et
Anticancer effect: Some evidences that bioactive compounds produced
by endophytes could be alternative approaches for discovery of novel drugs,
since many natural products from plants, microorganisms and marine sources were
identified as anticancer agents (Firakova et al.,
2007). The anticancer properties of several secondary metabolites from endophytes
have been investigated recently. Following, some examples of the potential of
endophytes on the production of anticancer agents are cited.
The diterpenoid Taxol (also known in the literature as paclitaxel) have generated
more attention and interest than any other new drug since its discovery, possibly
due to its unique mode of action compared to other anticancer agents (Gangadevi
and Muthumary, 2008; Firakova et al., 2007).
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 cancer, lung cancer
and refractory ovarian cancer (Cremasco et al., 2009).
Taxol was firstly isolated from the bark of trees belonging to Taxus family
(Taxus brevifolia), its most common source (Wani
et al., 1971). Nevertheless, these trees are rare, slow growing and
produce small amount of Taxol, which explain its high price in the market when
obtained by this natural source (Gangadevi and Muthumary,
2008). Besides, in the context of environmental degradation, the use of
plant source as unique option have limited the supply of this drug due to the
destructive collection of yew trees (Guo et al.,
2008). Several reports about Taxol anticancer properties were published
since its discovery (Lu et al., 2007; Kakolyris
et al., 2006; Peltier et al., 2006),
as well as other sources for production of Taxol have been investigated in the
last decade. The isolation of Taxol-producing endophyte Taxomyces andreanae
has provided an alternative approach to obtain a cheaper and more available
product via microorganism fermentation (Stierle
et al., 1993). After that, Taxol has also been found in a number
of different genera of fungal endophytes either associated or not to yews, such
as Taxodium distichum (Li et al., 1996),
Wollemia nobilis (Strobel et al., 1997),
Phyllosticta spinarum (Kumaran et al., 2008),
Bartalinia robillardoides (Gangadevi and Muthumary,
2008), Pestalotiopsis terminaliae (Gangadevi
and Muthumary, 2009), Botryodiplodia theobromae (Pandi
et al., 2010).
Another important anticancer compound is the alkaloid Camptothecin, a potent
antineoplastic agent which was firstly isolated from the wood of Camptotheca
acuminata Decaisne (Nyssaceae) in China (Wall et
al., 1966). Camptothecin and 10-hydroxycamptothecin are two important
precursors for the synthesis of the clinically useful anticancer drugs, topotecan
and irinotecan (Uma et al., 2008). Although its
potential use in medical treatments, the unmodified Camptothecin suffers from
drawbacks that compromise its applications due to very low solubility in aqueous
media and high toxicity (Li et al., 2006; Kehrer
et al., 2001). On the other hand, some Camptothecin derivatives retain
the medicinal properties and can show other benefits without causing over drawbacks
in some cases (Kusari et al., 2009a; Jew
et al., 1999). Therefore, it is desirable to develop strategies for
isolation, mixture separation and production of Camptothecin and its analogues
from novel endophytic fungal sources. The anticancer properties of the microbial
products Camptothecin and two analogues (9-methoxycamptothecin and 10-hydroxycamptothecin)
were already reported. The products were obtained from the endophytic fungi
Fusarium solani isolated from Camptotheca acuminate (Kusari
et al., 2009b). Several reports have described other Camptothecin
producing endophytes (Shweta et al., 2010; Liu
et al., 2010; Rehman et al., 2008; Amna
et al., 2006; Puri et al., 2005).
Since then, endophytes have been included inmany studies purposing new approaches
for drug discovery. Ergoflavin, a dimeric xanthene linked in position 2, belongs
to the compound class called ergochromes and was described as a novel anticancer
agent isolated from an endophytic fungi growing on the leaves of an Indian medicinal
plant Mimusops elengi (Sapotaceae) (Deshmukh et
al., 2009). Secalonic acid D, a mycotoxin also belonging to ergochrome
class, is known to have potent anticancer activities. It was isolated from the
mangrove endophytic fungus and observed high cytotoxicity on HL60 and K562 cells
by inducing leukemia cell apoptosis (Zhang et al.,
Phenylpropanoids have attracted much interest for medicinal use as anticancer,
antioxidant, antimicrobial, anti-inflammatory and immunosuppressive properties
(Korkina, 2007). Despite the phenylpropanoids belong
to the largest group of secondary metabolites produced by plants, reports showed
the production of such compounds by endophytes. The endophytic Penicillium
brasilianum, found in root bark of Melia azedarach, promoted the biosynthesis
of phenylpropanoid amides (Fill et al., 2010).
Likewise, two monolignol glucosides, coniferin and syringin, are produced not
only by the host plant, but were also recognized by the endophytic Xylariaceae
species as chemical signals during the establishment of fungus-plant interactions
(Chapela et al., 1991). Koshino and coworkers
characterized two phenylpropanoids and lignan from stromata of Epichloe typhina
on Phleum pretense (Koshino et al., 1988).
Lignans are other kinds of anticancer agents originated as secondary metabolites
through the shikimic acid pathway and display different biological activities
that make them interesting in several lines of research (Gordaliza
et al., 2004). Although their molecular backbone consists only of
two phenylpropane units (C6-C3), lignans show enormous structural and biological
diversity, especially in cancer chemotherapy (Korkina, 2007).
Podophyllotoxin and analogs are clinically relevant mainly due to their cytotoxicity
and antiviral activities and are valued as the precursor to useful anticancer
drugs like etoposide, teniposide and etopophos phosphate (Kusari
et al., 2009a; Kour et al., 2008).
The aryl tetralin lignans, such as podophyllotoxin, are naturally synthesized
by Podophyllum sp., 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 (Puri et al.,
2006). Novel microbial sources of Podophyllotoxin were reported from the
endophytic fungi Aspergillus fumigatus Fresenius isolated from Juniperus
communis L. Horstmann (Kusari et al., 2009b),
Phialocephala fortinii isolated from Podophyllum peltatum (Eyberger
et al., 2006) and Fusarium oxysporum from Juniperus
recurva (Kour et al., 2008).
Wagenaar et al. (2000) reported identification
of three novel cytochalasins, bearing antitumor activity from the endophyte
Rhinocladiella species. Extensive experiments identified these new compounds
as 22-oxa-12-cytochalasins. Torreyanic acid is an unusual dimeric quinone isolated
from the endophytic fungus Pestalotiopsis microspora from T. taxifolia
(Florida torreya) and was proven to have selective cytotoxicity 5 to 10
times more potent in cell lines that are sensitive to protein kinase C agonists
and causes cell death by apoptosis (Lee et al., 1996).
Gliocladicillins A and B were reported as effective antitumor agents in vitro
and in vivo, since they induced tumor cell apoptosis and showed significant
inhibition on proliferation of melanoma B16 cells implanted into immunodeficient
mice (Chen et al., 2009). Crude Extracts of Alternaria
alternata, an endophytic fungus isolated from Coffea Arabica L.,
displayed moderate cytotoxic activity towards HeLa cells in vitro, when
compared to the dimethyl sulfoxide (DMSO) treated cells (Fernandes
et al., 2009). The investigation of endophytic actinomycetes associated
with pharmaceutical plants in rainforest reported 41 microorganisms from the
genus Streptomyces displayed significant antitumor activity against HL-60 cells,
A549 cells, BEL-7404 cells and P388D1 cells (Li et al.,
2008c). The screening of endophytic fungi isolated from pharmaceutical plants
in China showed that 13.4% endophytes were cytotoxic on HL-60 cells and 6.4%
on KB cells (Huang et al., 2001). Finally, other
compounds with anticancer properties isolated from endophytic microbes were
reported such as cytoskyrins, phomoxanthones A and B, photinides A-F, rubrofusarin
B and (+)- epiepoxydon (Brady et al., 2000; Isaka
et al., 2004; Ding et al., 2009; Song
et al., 2004; Klemke et al., 2004).
Insecticidal effect: Several endophytes are known to have anti-insect
properties. Nodulisporic acids, novel indole diterpenes that exhibit potent
insecticidal properties against the larvae of the blowfly, work by activating
insect glutamate-gated chloride channels. The first nodulisporic compounds were
isolated from an endophyte, a Nodulisporium sp., from the plant Bontia
daphnoides. This discovery has since resulted in an intensive search for
more Nodulisporium sp., or other producers of more-potent nodulisporic
acid analogues (Demain, 2000). Insect toxins have also
been isolated from an unidentified endophytic fungus from wintergreen (Gaultheria
procumbens). The two new compounds, 5-hydroxy-2-(1-hydroxy-5-methyl-
4-hexenyl) benzofuran and 5-hydroxy-2-(1-oxo-5-methyl-4- hexenyl) benzofuran,
both show toxicity to spruce budworm and the latter is also toxic to the larvae
of spruce budworm (Findlay et al., 1997b). Another
endophytic fungus, Muscodor vitigenus, from a liana (Paullina paullinioides),
yields naphthalene as its major product. Naphthalene, the active ingredient
in common mothballs, is a widely exploited insect repellant. M. vitigenus
shows promising preliminary results as an insect deterrent and has exhibited
potent insect repellency against the wheat stem sawfly (Cephus cinctus)
(Daisy et al., 2002a, b).
As the world becomes wary of ecological damage done by synthetic insecticides,
endophytic research continues for the discovery of powerful, selective and safe
Antidiabetic effect: A nonpeptidal fungal metabolite (L-783,281) was
isolated from an endophytic fungus (Pseudomassaria sp.,) collected from
an African rainforest near Kinshasa in the Democratic Republic of the Congo
(Zhang et al., 1999). This compound acts as insulin
mimetic and unlike insulin, is not destroyed in the digestive tract and may
be given orally. Oral administration of L-783,281 to two mouse models of diabetes
resulted in significant lowering of blood glucose levels. These results may
lead to new therapies for diabetes (Zhang et al.,
Immunosuppressive effect: The endophytic fungus Fusarium subglutinans,
isolated from T. wilfordii, produces the immunosuppressive but noncytotoxic
diterpene pyrones subglutinol A and B (Lee et al.,
1995). Subglutinol A and B are equipotent in the mixed lymphocyte reaction
assay and thymocyte proliferation assay, with a 50% inhibitory concentration
of 0.1 μM In the same assay systems, the famed immunosuppressant drug cyclosporine
is roughly as potent in the mixed lymphocyte reaction assay and 104 more potent
in the thymocyte proliferation assay. Still, the lack of toxicity associated
with subglutinols A and B suggests that they should be explored in greater detail
(Lee et al., 1995). The Microbiology Department
at Sandoz Ltd. developed a computer-aided evaluation program to screen and evaluate
fungi for bioactivity. The program can recognize and eliminate from study common
fungi producing known compounds and thereby direct attention to the evaluation
of rare samples, which are more likely to produce metabolites with novel bioactivity.
This approach resulted in the discovery of the fungus Tolypocladium inflatum,
from which cyclosporine, a hugely beneficial immunosuppressant, was isolated
(Borel and Kis, 1991). This example perfectly depicts
the current aim of many investigators to seek out rare endophytes from interesting
and uncommon hosts and environments (Strobel and Daisy,
BIOACTIVE COMPOUNDS PRODUCTION BY BIOTRANSFORMATION PROCESS
Biotransformation can be defined as the use of biological systems to produce
chemical changes on compounds that are not their natural substrates (Borges
et al., 2008). The microbial growth, sustenance and reproduction
depends on the availability of a suitable form of reduced carbon source, used
as chemical energy, which under normal conditions of culture broth are the common
sugars. Nevertheless, microorganisms are believed to have no limit to adapt
to new environments and to metabolize various foreign substrates to carbon and
nitrogen sources (Doble et al., 2004). A molecule
can be modified by transforming functional groups, with or without degradation
of carbon skeleton. Such modifications result in the formation of novel and
useful products not easily prepared by chemical methods (Borges
et al., 2009). The biotransformation process provides a number of
advantages over chemical synthesis. The process can be carried out under mild
conditions like ambient temperature and without the need of high pressure and
extreme conditions, thus reducing undesired byproduct, energy needs and cost
(Suresh et al., 2006). The region-and stereo-selectivity
of the process allows the production of enantiomerically pure compounds, eliminating
the need for complicated separation and purification steps (Borges
et al., 2008). Besides, the reactions occur under ecologically acceptable
conditions, with lower emission of industrial resides and production of biodegradable
resides and products, thus reducing the environmental problems (Bicas
et al., 2009; Aleu and Collado, 2001).
Finally, the products obtained by biotransformation process can be labeled as
natural. On the other hand, chemical synthesis often result in environmentally
unfriendly production processes and lacks substrate selectivity, possibly causing
the formation of undesirable reaction mixtures and reducing process efficiency
and increasing downstream cost (Longo and Sanroman, 2006
Therefore, biotransformation is a useful method for production of novel compounds;
enhancement in the productivity of a desired compound; overcoming the problems
associated with chemical analysis
; leading to basic information to elucidate the
biosynthetic pathway (Suresh et al., 2006
). For this
reason, biotransformation using microbial cultures and/or their enzymatic systems
alone has received increasing attention as a method for the conversion of lipids,
monoterpenes, diterpenes, steroids, triterpenes, alkaloids, lignans and some synthetic
chemicals, carrying out stereospecific and stereoselective reactions for the production
of novel bioactive molecules with some potential for pharmaceutical and food industries
(Borges et al., 2009
et al., 1996
; Pimentel et al., 2010
Endophytes are a poorly investigated group of microorganisms that represent an abundant and dependable source of bioactive and chemically novel compounds with potential for exploitation in a wide variety of medical, agricultural and industrial areas. The mechanisms through which endophytes exist and respond to their surroundings must be better understood in order to be more predictive about which higher plants to seek, study and spend time isolating micro floral components. This may facilitate the product discovery processes. Although work on the utilization of this vast resource of poorly understood microorganisms has just begun, it has al ready become obvious that an enormous potential for organism, product and utilitarian discovery in this field holds exciting promise. This is witnessed by the discovery of a wide range of products and microorganisms that already hold inkling for future prospects as mentioned in this report. However, the application of microorganisms by the food and pharmaceutical industries to obtain compounds of interest is still modest, considering the great availability of useful microorganisms.
The authors acknowledges to Management of Malankara Catholic College (MCC) for their all efficient support for our research. We thank Research Team of Interdisciplinary Research Centre (MCC), for critically reviewing the manuscript and helpful discussions. We express appreciation to Mr. S. Murugan providing financial support for some of the work reviewed in this report.
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