Cream 2 1 3

Current Research in Environmental & Applied Mycology Doi 10.
5943/cream/2/1/3
Biology of Endophytic Fungi
Selim KA1,*, El-Beih AA1, AbdEl-Rahman TM2 and El-Diwany AI 1

1
Chemistry of Natural and Microbial Product Department, National Research Center, 12622 Dokki, Cairo, Egypt.
2
Botany Department, Faculty of Science, Cairo University, Giza, Egypt.
Selim KA, El-Beih AA, AbdEl-Rahman TM, El-Diwany AI. 2012 – Biology of Endophytic Fungi.
Current Research in Environmental & Applied Mycology 2(1), 31–82, Doi 10.5943/cream/2/1/3
Endophytic fungi that are residing asymptomatically in internal tissues of all higher plants are of
growing interest as promising sources of biologically active agents. This review focuses on the
biology of endophytic fungi, their discovery, isolation, identification, and diversity and their
biological activities in environmental and agricultural sustainability. It also considersand their
medicinal applications especially in the production of anticancer, antimicrobial, antioxidant, and
antiviral compounds. Endophytic fungi are one of the most creative groups of secondary metabolite
producers that play important biological roles for human life. They are potential sources of novel
natural agents for exploitation in the pharmaceutical industry, agriculture, and in environmental
applications.
Key words – Biological Roles – Ecology – Endophytic Fungi – Identification – Isolation –

Secondary Metabolites
Article Information
Received 30 January 2012
Accepted 4 May 2012
Published online 20 June 2012
*Corresponding author: Khaled A. Selim – e-mail – elkas_sci@yahoo.com
Introduction actinomycetes, and fungi). The discovery of

natural products involves isolation, structural
Natural Products as Important Sources in elucidation and establishing the bio-synthetic
the Drug Discovery Process pathway of the secondary metabolites. This is
There is a need to search new an area of considerable interest to scientists
ecological niches for potential sources of due to the structural diversity, complexity and
natural bioactive agents for different pharma- various bioactivities of isolated compounds.
ceutical, agriculture, and industrial applica- Crude natural products have been used directly
tions; these should be renewable, eco-friendly as drugs which were low cost and important
and easily obtainable (Liu et al. 2001). Natural sources of traditional medicines. They also
products discovery have played major role in provided the basic chemical architecture for
the search for new drugs, and is the most deriving semi-synthetic natural products
potent source for the discovery of novel (Suryanarayanan et al. 2009).
bioactive molecules. Natural products are The role of natural products in
chemical compounds derived from living discovery of new therapeutic agents can be
organisms. The most prominent producers of demonstrated by an analysis of the number and
natural products can be found within different sources of bioactive agents. There are at least
groups of organisms including plants, animals, 200,000 natural metabolites with various
marine macro-organisms (sponge, corals and bioactive properties (Bérdy 2005). According
algae), and microorganisms (bacteria, to Cragg et al. (1997) anti-cancer and anti-
31
Current Research in Environmental & Applied Mycology Doi 10.5943/cream/2/1/3
Fig. 1 – Distribution of Natural Products as Drugs New Chemical Entities in Time Frame 1981-
2006
Adapted from (Newman et al. 2003) (Newman & Cragg 2007)
“B” Biological; usually a large (> 45 residues) peptide or protein, generally isolated from an organism/cell line or
produced by biotechnological means in a surrogate host; “N” Natural product; “ND” Derived from a natural product,
usually a semisynthetic modification; ”S” Totally synthetic drug, mostly found by random screening or modification of
an existing agent; “S*” Made by total synthesis, but the pharmacophore is/was from a natural product; “V” Vaccine;
“NM” Natural Product mimic.
infective agents that were approved as drugs peptidic antibiotic compounds like the
were more than 60% from natural origin. penicillin V and cephalosporin C, the
Between 1981-2006, about 100 anti- polyketide lovastatin used in cholesterol
cancer agents have been developed, 25% of treatment and the antibacterial terpenoid
them were natural product derivatives, 18% fusidic acid (Fig 2).
were natural product mimics, 11% candidates
were derived from a natural product Fungi as Producers of Biologically Active
pharmacophore, and 9% were pure natural Metabolites
products. Actually 47% of total anticancer More than 20,000 bioactive metabolites
drugs and 52% of new chemicals introduced are of microbial origin (Bérdy 2005). Fungi are
into the market are of natural origin (Chin et al. among the most important groups of eukaryotic
2006, Newman & Cragg 2007). In the USA organisms that are well known for producing
more than 50% of prescribed drugs are natural many novel metabolites which are directly
products or semi-synthetic derivatives. In addi- used as drugs or function as lead structures for
tion, a number of chemicals used in crop prote- synthetic modifications (Kock et al. 2001,
ction are also of natural origin (Schneider et al. Bode et al. 2002, Donadio et al. 2002, Chin et
2008). Thus natural sources make a very signi- al. 2006, Gunatilaka 2006, Mitchell et al. 2008,
ficant contribution to the health care) Fig.1. Stadler & Keller 2008). The success of several
Since, the discovery of potent antibiotic medicinal drugs from microbial origin such as
against Gram-positive bacteria, penicillin from the antibiotic penicillin from Penicillium sp.,
culture of fungus Penicillium notatum by the immunosuppressant cyclosporine from
Fleming in 1929, the search for new drugs Tolypocladium inflatum and Cylindrocarpon
from microbial origin started. Koehn & Carter lucidum, the antifungal agent griseofulvin from
(2005) and Newman & Cragg (2007) reported Penicillium griseofulvum fungus, the
many of secondary microbial metabolites cholesterol biosynthesis inhibitor lovastatin
which show potent pharmaceutical application from Aspergillus terreus fungus, and β-lactam
against various diseases. This included the antibiotics from various fungal taxa, has shifted
therapeutically used ergotamine, the the focus of drug discovery from plants to
immunosuppressive peptide cyclosporine A, microorganisms.
32
Fig. 2 – Structure of some biological active microbial metabolites
Suryanarayanan et al. (2009) discussed cancer activities. Also, fungal metabolites are
many fungal secondary metabolites with important in agriculture applications (Anke &
various chemical structures and their wide Thines 2007).
ranging biological activities and this reflects It has been estimated that there may be
the high synthetic capability of fungi 1.5 million fungal species, while only about
(Suryanarayanan & Hawksworth, 2005). About 100,000 species are presently known
1500 fungal metabolites had been reported to (Hawksworth 2004). Only a few taxa have
show anti-tumor and antibiotic activity (Peláez tested for their biological applications
2005) and some have been approved as drugs. including their ability for drug production and
These include micafungin, an anti-fungal biological control. Thus it seems that the
metabolite from Coleophoma empetri discovered percentage of economically
(Frattarelli et al. 2004), mycophenolate, a valuable fungal metabolites is small.
product of Penicillium brevicompactum, which Soil fungi have been the most studied of
is used for preventing renal transplant rejection fungi, and typical soil genera such as
(Curran & Keating 2005), rosuvastatin from Acremonium, Aspergillus, Fusarium and
Penicillium citrinum and P. brevicompactum, Penicillium have shown ability to synthesis a
which used for treating dyslipidemias (Scott et diverse range of bioactive compounds. More
al. 2004) and cefditoren pivoxil, a broad than 30% of isolated metabolites from fungi
spectrum antibiotic derived from are from Aspergillus and Penicillium (Bérdy
Cephalosporium sp. (Darkes & Plosker 2002). 2005). Fungi however were usually obtained
Others include derivatives of fumagillin, an from the same ecological niche using the same
antibiotic produced by Aspergillus fumigates fungal isolation methods. Therefore the the
(Chun et al. 2005), and illudin-S, a same fungal strains were re-isolated and this
sesquiterpenoid from Omphalotus illudens lead to the re-discovery of known compounds
(McMorris et al. 1996) which exhibits anti- as the same taxa produce the same metabolites.
33
Fig. 3 – Taxol, anticancer drug produced by many endophytic fungi.
Dreyfuss & Chapella (1994) assumed that intercellular spaces of the tissues and its seems
different environmental factors including that they may penetrate the living cells (Strobel
different physical conditions and different 2003). Endophytes form inconspicuous infec-
biological situations in the nature, may change tions within tissues of healthy plants for all or
behavior of microbes and favor the production nearly all their life cycle and their host tissues
of diverse range of secondary metabolites, so appear symptomless, and they remain asympto-
the search for alternatively unexplored matic for many years and only become parasi-
ecological niches should be targeted. The tic when their hosts are stressed (Firáková et al.
investigation of fungal isolates from ecological 2007, Limsuwan et al. 2009). Endophytic fungi
niches other than soil may lead to investigating are an ecological, polyphyletic group of highly
novel fungal groups with novel and diverse of diverse fungi, mostly belonging to ascomycetes
secondary metabolites. Fungi occupy every and anamorphic fungi (Huang et al. 2001,
living and non-living niche on earth, this Arnold 2007).
includes those in the thermal vents, in deep Approximately, there are near to
rock sediments, and in desert as well as marine 300,000 plant species on earth and each
environments (Strobel 2003). Some of unex- individual plant is the host to one or more
plored fungal groups derived from such endophytes, and many of them may colonize
ecosystems are endophytic fungi, fresh-water certain hosts. It has been estimated that there
fungi, and marine-derived fungi (Dreyfuss & may be as many as one million different
Chapella 1994). In this review we will focus endophytic fungal taxa, thus endophytes may
and concentrate on endophytic fungi that reside be hyperdiverse (Petrini 1991, Strobel & Daisy
in plants, and the importance of their secondary 2003, Huang et al. 2007). Endophytesmay
metabolites. produce a plethora of bioactive metabolites that
may be involved in the host-endophyte
Endophyte relationship (Strobel 2003), and may serve as
Plants may serve as a reservoir of large potential sources of novel natural products for
numbers of microorganisms known as endo- exploitation in medicine, agriculture, and
phytes (Bacon & White 2000). Endophytes are industry (Bacon & White 2000, Strobel &
microorganisms (mostly fungi and bacteria) Daisy 2003). The described populations of
that inhabit plant hosts for all or part of their endophytic strains are few, which means the
life cycle. They colonize the internal plant opportunity to find new strains and targeting
tissues beneath the epidermal cell layers natural products from endophytic
without causing any apparent harm or sympto- microorganisms that colonize plants in
matic infection to their host, living within the different niches and ecosystems is great.
34
Fig. 4 – Oocydin A, antifungal agent isolateded from Serratia marcescens.
Discovery the Importance of Endophytic 1996). Furthermore, several other P.

Fungi microspora isolates were obtained from bald
The importance of endophytes had been cypress in South Carolina and were also shown
demonstrated over a long period as potential to produce taxol (Li et al. 1996). This was the
sources of pharmaceutical leads, as many of first indication that other endophytes than T.
endophytic fungi were reported to produce andreanae residing in plants other than Taxus
novel bioactive metabolites such as spp. were producing taxol. Numerous reports
antimicrobial, anticancer, and antiviral agents. have shown that many of other endophytic
The discovery of taxol producing fungi fungi such as Pestalotiopsis guepini and
increased the importance of endophytes and Periconia sp. also produce taxol (Li et al. 1998,
shifted natural products research to endophytic Strobel et al. 1997). Also endophytic Fusarium
fungi. solani isolated from Taxus chinensis and other
Taxol (Fig 3), a highly functionalized common endophytic genera such as Alternaria
diterpenoid, is found in each yew (Taxus) and Aspergillus isolated from Ginkgo biloba
species, but was originally isolated from Taxus and Podocarpus sp. respectively, had been
brevifolia (Suffness 1995, Wani et al. 1971). reported as producers of taxol (Kim et al. 1999,
This compound is the world‟s first billion Sun et al. 2008, Liu et al. 2009).
dollar anticancer drug, and it is used for Thus, the presence of a microbial
treatment of ovarian and breast cancers, but source of the drug could eliminate the need to
now it is used to treat a number of other human harvest and extract the slow growing and
tissue-proliferating diseases as well. Its cost relatively rare yew trees, and the price for the
makes it unavailable to the most of world‟s drug would also be reduced and the drug will
people (Nicolaou et al. 1994). It was suggested be available to cancer patients, since taxol
by Stierle et al. (1993) that yew trees might could be produced via fermentation in the same
support certain endophytic microorganisms way that penicillin is fermented (Strobel 2003).
that may also synthesize taxol. However, despite the promised concerning the
In the early 1990s, a novel taxol- production of taxol by endophytes, this has not
producing endophytic fungus, Taxomyces materialized into industrial production. It may
andreanae, was isolated from Taxus brevifolia be that the fungi carry residue of taxol over
(Strobel et al. 1993). This set the stage for a from the plant or rapidly lose their abilities to
more comprehensive examination of the ability produce taxol in vitro.
of other Taxus species and other plants to yield
endophytes producing taxol. An examination Isolation and Cultivation of Endophytes
of the endophytes of Taxus wallichiana yielded Fungi from Plants
the endophytic fungus Pestalotiopsis Isolation of endophytes is a critical
microspora, and a preliminary screening step, because it requires sensitivity to recover a
indicated that it produced taxol (Strobel et al. maximum number of colonized endophytes and
35
should be accurate enough to eliminate the of the medicinal properties of this plant.
epiphytic microbes which are present on the For example, the endophtic fungus
plant surface. Endophytes can be isolated from Fusarium proliferatum possessing
various plant parts such as seeds, leaves and antimicrobial activity, was isolated from
stems. The collected plants for studying traditional Chinese medicinal plant
endophytic communities should look Celastrus angulatus (Ji et al. 2005).
apparently healthy and disease free plant, i.e. 3. Plants that are endemic, having an
they do not display any visual symptoms of unusual longevity, or have occupied a
diseases, in order to minimize the presence of certain ancient land mass, are appropriate
plant pathogenic and saprobic species, and to for study. An endophytic fungus
prevent the isolation of localized pathogenic Chaetomium globosum, isolated from leaf
endophytic microorganisms (Strobel 2003, of endemic plant Maytenus hookeri,
Strobel & Daisy 2003). which is only distributed in areas of
Yunnan, China, was found to produce
Selection of Plant Material Chaetoglobosin B which showed anti-
It is important to understand the methods tuberculosis activity (Ni et al. 2008).
and rationale used to provide the best 4. Plants growing in areas of great
opportunities to isolate endophytes, since the biodiversity also have the potential for
number of plant species in the world is so great housing endophytes with great diversity.
and each individual plant may be host to Kumaresan & Suryanarayanan (2001)
numerous endophytes. Creative and imagina- found that many endophytic fungi
tive strategies must therefore be used to quick- colonized trees in mangrove forests.
ly narrow the search for the host plants for 5. Plants surrounded by pathogen infected
isolation and target endophytes displaying bio- plants, and showing no symptoms are
activity (Mittermeier et al. 1999, Strobel 2003, more likely to lodge endophytes
Strobel & Daisy 2003). Several criteria must be possessing antimicrobial activity than
considered in plant selection strategy, and these other plants. For example
are as follows (Strobel & Daisy 2003): Tuntiwachwuttikul et al. (2008) reported
1. Plants from a unique ecological an endophyte showing antimicrobial
environmental niche, and growing in activity against plant pathogen
special habitats, especially those with an Colletotrichum musae.
unusual biology and possessing novel 6. Young plant tissue is more suitable for
strategies for survival should seriously be isolation of endophytic fungi than older
considered for study. Strobel et al. tissues which often contain many
(1999a) showed that an aquatic plant, additional fungi that make isolation of
Rhyncholacis penicillata, which lives in slow growing fungi difficult to isolate.
harsh aquatic environment which may be The collected plant samples are stored at
constantly wounded by passing rocks and 4°C until the isolation procedure is
other debris, resists infection by common carried out, and isolation should be as
oomyceteous fungi (water molds that are soon as possible after collection to avoid
phytopathogenic) that cause disease. The contamination by air microspora (Bacon
possibility that endophytes associated & White 1994).
with this aquatic plant may produce
antifungal agents that protect the plant Acquiring endophytes which may
from attack by pathogenic fungi is display bioactivity, needs selection of plant
feasible. A novel antioomycetous species that may be of interest because of their
compound, oocydin A (Fig 4) was unique biology, age, endemism, ethnobotanical
discovered from the endophytic strain history, and/or environmental setting. Yu et al.
Serratia marcescens from this plant. (2010) showed that medical plants and plants
2. Plants that have an ethnobotanical in special environments were frequently
history, and are used for traditional studied for screening for presence of
medicines should be selected for study, as endophytes that produce antimicrobial agents
inhabiting endophytes may be the source (Fig 5).
36
Fig. 5 – Proportion of biologically active endophytic fungal isolates from different sources with
antimicrobial activities. Adapted from: (Yu et al. 2010).
Isolation of Endophytic Fungi flasks over a three months period to promote

The most important step for the sporulation of morphospecies (Fig 6).
isolation of endophytic fungi that reside in Endophytes are diverse and often grow
plant tissues is surface sterilization and the readily in culture. With recent technological
plant parts under investigation should be cut advances, the use of culture-free methods
into small pieces to facilitate sterilization and promises to discover ever-greater diversity and
isolation processes. To achieve complete to expand our understanding of the structure of
surface sterilization, there are various methods the fungal tree of life. One particularly useful
to eliminate most of the epiphytic fungi from aspect of culture-free methods may be to show
the exterior tissues and encourage the growth that particular fungi are present in an
of the internal mycota, according to the type of environment, thus leading endophyte
tissue as well as its location (Strobel 2003, researchers to optimize culturing conditions as
Strobel & Daisy 2003). a means to capture those fungi in vitro. Such
efforts are critical for establishing voucher
Identification of Endophytic Fungi specimens, which in turn can be used to
Identification of endophytic fungi based empirically assess species interactions, as raw
is mainly on morphological methods, using materials for bioprospecting or biological
characters of the phenotype of the fungal control, and as the basis for future research in
culture, i.e. colony or hyphae, the characters of systematics or genomics. Because many
the spore, or reproductive structure if these endophytes do not sporulate in culture, and
features were discernible (Wei 1979, thus are classified only as mycelia sterilia, they
Carmichael et al. 1980, Barnett & Hunter are not welcome at most established culture
1998). Most of endophytic fungi belong to the collections. Depositories are needed to house
ascomycetes and asexual fungi (Huang et al. and maintain vouchers of these fungi, and to
2001), but some endophytic isolates may fail to curate their ecological data (site of origin; host
produce reproductive structures even after plant; season; tissue type). Both the specimens
several months. These isolates cab be themselves and the data regarding their
encouraged to sporulate on medium contains recovery have tremendous intrinsic value,
stripes or extract of host plant (Matsushima (Arnold 2007).
1971). Sterile isolates should be checked According to Huang et al. (2008a)
regularly for fruiting bodies over a period of 3- sterile mycelia are widely distributed among
4 months and the isolates that failed to plant hosts as they were found in 27 medicinal
sporulate are referred to as mycelia sterilia, ar plants of 29 host plants used for screening for
divided into different morphotypes according endophytic fungi. High relative frequencies of
to their culture characteristics. These groups of 27% of endophytic fungal isolates from 29
fungi are considerably common in endophytes medicinal plants were sterile (Fig7). Many
studies (Lacap et al. 2003). Guo et al. (1998) variable proportions of mycelia sterilia ranging
reported other methods using twigs in conical from 11% to 54% had been
37
Fig. 6 – Assortment of ascomycetous endophytic fungi recovered from foliage of angiosperms and
conifers in North America and Panama, Adapted from: (Arnold 2007).
reported (Petrini et al. 1982; Garcia & isolates, and to study phylogeny of endophytic
Langenheim 1990, Fisher et al. 1994, Taylor et fungi, about 24% of endophytic isolates from
al. 1999, Fröhlich et al. 2000, Guo et al. 2000). three Attemisia species were sterile, and with
Thus, the common problem concerning aid of molecular techniques the phylogeny of
identification of endophytic fungi are that some 34 endophytic fungi were studied, including
of endophytes could not be identified to species identification of some sterile species and
or genus level (Gamboa & Bayman 2001, confirmation of some morphological identified
Promputtha et al. 2005a & b), and having many species, using amplification of ITS1, 5.8S and
non-identified mycelia sterilia, raises the ITS2 fragments of rDNA.
importance of use modern molecular Molecular techniques can show hidden
techniques that could be the best alternative to diversity and help reveal identities and
identify this taxa. diversity of sterile mycelia. However, the
careless use of named GenBank sequences
Molecular Characterization of Endophytic without questioning whether their
Fungi identifications are correct has lead to many
Molecular approaches have been used species in endophyte studies being wrongly
to resolve problems in fungal taxonomy and for named (Ko Ko et al. 2011). Extreme caution
direct detection and identification of fungi must be taken when using named sequences
within natural habitats (Rollo et al. 1995, Ma et from GenBank as these are often wrongly
al. 1997, Zhang et al. 1997, Liew et al. 1998, named (Cai et al. 2009, Koko et al. 2011a,b).
Ranghoo et al. 1999). The most frequently
accountered problem in endophytic fungi is the Ecology and Biodiversity of Endophytes
presence of mycelia sterilia, making their Endophytic fungi represent an
morphological identification difficult (Guo et important and quantified component of fungal
al. 2000). Ribosomal DNA sequence analysis biodiversity, and are known to have an effect
using specific PCR primers to amplify rDNA on and be affected by plant community
fragments of endophytes was used to validate diversity and structure (Sanders 2004, Gonthier
the morphospecies of different groups of et al. 2006, Krings et al. 2007). Almost all
mycelia sterilia, and to resolve the vascular plant species examined to date were
identification problem associated with found to harbor endophytes. Endophytes have
endophytic fungi (Doss & Welty 1995, Lacap been also recorded colonizing marine algae and
et al. 2003) (Fig 8). grasses, mosses and ferns (Tan & Zou 2001).
According to Huang et al. (2009) rDNA Endophytes are present in virtually all organs
sequence analysis is frequently used to confirm of a given plant host, and some are seed-borne
morphological identification of endophytic (Hyde & Soytong 2008). Endophytes can be
38
Fig. 7 – Relative frequencies of different endophytic taxa isolated from 29 Chinese medicinal plants
showing high percent of Sterile Mycelia, Adapted from (Huang et al. 2008a).
transferred from plant to plant via seeds (Aly et complex bio-chemical interaction between host
al. 2011). The mycelium of the fungus then and its associated endophytes, raising enor-
grows into the sheath, stem, and leaf tissues, mous variability between endophytes, through
finally enters the flowering stem and seeds mutation, genetic crossing, or by unsubstan-
(Firáková et al. 2007). The endophyte is passed tiated mechanisms such as developing genetic
to the next generation of plants through the system allowing transferring of information
seed, for instance asexual Acremonium grass between themselves and host plants (Tan &
endophytes are dispersed exclusively through Zou 2001, Firáková et al. 2007).
the seeds of their hosts (Tan & Zou 2001). Host-recurrence refers to the frequent
A variety of relationships can coexist or predominant occurrence of endophytes on a
between endophytes and their host plants, particular host or a range of plant hosts, and
ranging from mutualism or symbiosis to endophytes can also found infrequently on
antagonism or slightly pathogenic (Schulz & other host plants in the same habitat (Zhou &
Boyle 2005, Arnold 2007, Purahong & Hyde Hyde 2001). A single endophytic species may
2011). The host-endophyte relationships can be form relationships with two or many related
described in terms of host-specificity, host- host plants, but found in a preference for one
recurrence, host-selectivity, or host preference particular host, and this phenomenon is defined
(Zhou & Hyde 2001, Cohen 2006). as host selectivity (Cohen 2006).
Host-specificity (a phenomenon in The term host-preference is more
endophytes-plant interaction) is a relationship frequently used to indicate a common occurre-
in which microorganism is restricted to a single nce or uniqueness of occurrence of endophytes
host or a group of related species, and such to particular host, and also used to indicate the
specificity implies that complex biochemical difference in endophytic community composi-
interaction occur between host and its tion and relation frequencies from different
associated endophytes (Holliday 1998, Strobel host plants (Suryanarayanan & Kumaresan
2003, Strobel & Daisy 2003). Host-specific 2000). Endophytes are also able to colonize
strain formation can be interpreted as a form of multiple host species of the same plant family
ecological adaptation. It can be accepted that within the same habitat, and the distribution of
morphologically indistinguishable strains of some endophytes can be similar in closely
the same species will exhibit different physio- related plant species (Huang et al. 2008a).
logical traits that may be host-related (Petrini Colletotrichum, Phoma, Phomopsis and
1991). For example Pestalotiopsis microspora Phyllosticta endophytes have a wide host range
is one of the most commonly found endophytes and colonize several taxonomically unrelated
in Taxa species (yews). Extracts of 15 isolates plant hosts (Pandey et al. 2003, Jeewon et al.
of Pestalotiopsis microspora, obtained from at 2004, Murali et al. 2006, Sieber 2007, Hyde et
least four continents, were examined and it was al. 2009, Udagaya et al. 2011, Wikee et al.
observed that no two chromatograms were 2011) suggesting that they have developed
identical. This is an indication that there is adaptations to overcome different types of host
39
Fig. 8 – The phylogenetic context of endophyte symbioses: relative abundance of five classes of
Ascomycota among endophytes isolated from three different plant families in southeastern Arizona,
USA. Hosts representing the Fagaceae (Quercus spp.; N=44 isolates, dominated by the
Sordariomycetes), Pinaceae (Pinus ponderosa; N=111 isolates, dominated by the Leotiomycetes),
and Cupressaceae (Cupressus arizonica and Platycladus orientalis; N=42 isolates, dominated by the
Dothideomycetes) differ markedly in the relative abundance and dominance of each class. The
predominant classes listed here also dominate endophyte communities associated with these host
families in other sites, including mesic semideciduous forest (North Carolina; all families) and
boreal forest (Québec; Pinaceae and Cupressaceae), Adapted from: (Arnold 2007).
defenses. of the endophyte would also result in a change

in its metabolite profile. Also, the
Effect of Environment on Endophytes environmental conditions which effect on host
Environmentally, the endophyte may be plant growth, influence the number and variety
metabolically aggressive by affecting host of endophytic populations, and affect on
defense chemicals (Cabral et al. 1993, Peters et metabolites produced by endophytes.
al. 1998, Schulz et al. 1999). Such a hostile The difference in endophytes,
environment may account for the evolution of difference in their metabolic profile, and hence
the potentially increased synthetic ability of the difference in their biological activity even if
endophytes. This perhaps explains the apparent between the same isolates of same species,
anomaly observed when a species of endophyte might be related to the chemical difference of
isolated from a plant host produces a bioactive host plants (Paulus et al. 2006). This depends
compound but fails to do so when isolated on the environment, and shows the importance
from another plant species (Li et al. 1996). The of studying host-endophytes relationships, and
herbicidal activity of secondary metabolites of the effect of host plants on endophytic
an endophytic Phyllosticta capitalensis metabolites production. Hence, the importance
differed with the plant host from which the of the host plant as well as the ecosystem were
endophyte was isolated. This probably means influencing endophytes metabolites production,
that the plant host (and ultimately its and affect on biological activitites of
metabolism) influences the synthetic ability of endophytes. More attention should be given to
an endophyte. This indicates that studying the endophytic biodiversity, the
bioprospecting for endophyte natural products chemistry and bioactivity of endophytic
should be host plant based as opposed to fungal metabolites, and the relation between
taxon based. In this regard, the endophyte-plant endophytes and their host plants (Tan & Zou
host association could also be exploited in 2001, Schulz et al. 2002).
enhancing the production of useful metabolites
by the plant host (Wang et al. 2004). Host - Endophytes interaction
Endophytes residing in the host tissue There is a complex relationship
in a symptomless state or one that may be between endophytes and their host plants.
beneficial to its host may turn into a pathogen Host-endophyte interactions can range from
in response to some environmental cue mutualism through commensalism to
(Hendry et al. 2002); such a shift in the nature parasitism, as the phenotypes of the
40
interactions are often plastic, depending on the variable and influenced by environmental
genetic dispositions of the two partners, their factors, nutritional status and developmental
developmental stage and nutritional status, but stages of the partners. Hence, commensalism
also on environmental factors (Johnson et al. and mutualism require a sophisticated balance
1997, Redman et al. 2001, Schulz & Boyle between the defense responses of the plant and
2005). Commensalism provides benefit to the the nutrient demand of the endophyte (Kogel et
endophyte by enabling an undisturbed existen- al. 2006).
ce and nutrient supply without affecting the Endophytes possess structural similari-
host. The mutual relationship benefits the ties with pathogens and both possess many of
endophytic fungi through provision supply of same virulence factors, such as production of
energy, nutrients, shelter as well as protection phytotoxic metabolites and exoenzymes which
from environmental stress. On the other hand are necessary to infect and colonize the host, so
fungal endophytes indirectly benefit plant endophytes are object to the host‟s non-self
growth by producing special substances mainly recognition, i.e. host can respond with the same
secondary metabolites and enzymes, which are defense reactions as to a pathogen (Fig 10).
responsible for the adaptation of plants to Additionally, cell wall penetration by fungi is
abiotic stresses such as light, drought and normally accompanied by the release of plant-
biotic stresses, such as herbivore, insect and elicitor. Hence, endophytes must avoid or
nematode attack or invading pathogens (Barz et overcome non-specific resistance responses to
al. 1988, Kogel et al. 2006). achieve successful penetration by reprogram-
Under certain conditions endophytes ming the invaded cell to accommodate infec-
may become parasitic, and become pathogens tion structures and to maintain host cell integri-
causing symptomatic infection (Brown et al. ty for a long-lasting interaction (Kogel et al.
1998) and vice versa (ref) Mutation of patho- 2006).
genic Colletotrichum magna resulted in the Finally, for mutualistic interactions, it is
loss of a virulence factor and transformation not yet clear to what extent friendly recognition
into an endophytic fungus (Freeman & Rodri- overbalances unfriendly recognition. The avoi-
guez 1993). Hence, parasitism is an exception dance and modification of elicitors circumvents
in plant-endophytes interactions; it can be recognition, or antagonistic pathways are enga-
regarded as an unbalanced status of a symbio- ged to switch off plant defense. Under this
sis when the host is stressed and physiological view, mutualistic interactions between endo-
or ecological conditions favors virulence phytic invaders and a host plant are deciphered
(Müller et al. 2005, Schulz & Boyle 2005, as a balance, under environmental, physiolo-
Kogel et al. 2006). Endophytes of certain plant gical and genetic control, that results in fitness
could be a pathogen of other plants, depending benefits for both partners, and parasitism is an
on the balance between pathogenicity and unbalanced symbiosis (Stracke et al. 2002,
endophytism of the microorganism in the Zipfel & Felix 2005, Kogel et al. 2006).
different hosts (Saikkonen et al. 2004). Moricca & Ragazzi (2008) indicates that the
Schulz & Boyle (2005) proposed that type of interaction between an endophyte and a
asymptomatic colonization of endophytes is a plant is controlled by the genes of both
balanced antagonistic interaction between host organisms and modulated by the environment.
plant and endophyte (Fig 9), and as long as
endophytic virulence and plant defense are Biological Role of Endophytes
balanced the interaction remains asymptomati. Endophytes play vital roles in various
Once the host-endophyte interaction becomes aspects of life varying from its effects on host
imbalanced either disease results in the host plants to its effects to environmental and
plant or the plant defense machinery kills the human life. Endophytes are capable of
pathogenic endophytic fungus. Whether the synthesizing bioactive agents that can be used
interaction is balanced or imbalanced depends by plants for defense against pathogens and/or
on the general status of the partners, the stimulating plant growth, and other agents have
virulence of the fungus, and the defenses of the been proven useful for novel drug discovery
host, and both virulence and defense being process.
41
Fig. 9 – Hypothesis: a balance of antagonisms between endophytic virulence and plant defense
response results in asymptomatic colonization, Adapted from: (Schulz & Boyle 2005).
Roles of Endophytes on Host-Plants positive indirect effects on the other well-

Plants are affected by endophytes in known functions, such as greater stress
various ways, and the potential functions of tolerance or pathogen resistance in plants
endophytes have not been clearly defined, but (Kageyama et al. 2008).
in the most cases, the presences of endophytic The mechanisms of enhancement of
microorganisms in the host plants are nutrient uptake by plants colonized by
beneficial to their host plants. Endophytes can endophytes have remained elusive, but the
actively or passively promote the plant growth arguments which are often used in support of
through a variety of mechanisms, as mycorrhizal nutrient uptake may be applied: as
endophytic metabolites provide a variety of extramatrical mycelium extending from the
fitness to host plants enhanced by increasing host roots may increase the surface area and
plant resistance to biotic and abiotic stresses, as therefore increase host access to soil nutrients.
well as enhance plant growth (Fig 11). Many Barrow & Osuna (2002) present another
endophytes are reported to be capable of interesting possibility, in root exclusion
nitrogen (N) fixation, solubilization of phos- experiment that controlled sources of P in the
phate, enhance uptake of phosphorus (P), substrate, they showed that Atriplex canescens
production of siderophores, ACC deaminase, inoculated with endophytic fungus Aspergillus
and plant hormones such as auxin, abscisins, ustus may have gained access to phosphate
ethylene, gibberellins, and indole acetic acid otherwise it will be unavailable to the host
(IAA), which are important for plant growth plant.
and development regulation (Baldani et al. An endophytic basidiomycet, Piriform-
1986, Goodman et al. 1986, Barraquio et al. ospora indica may serve as a smart model
1997, Gasoni & Gurfmkel 1997, Malinowski et system to elucidate the mechanisms of nutrient
al. 1999, Zou et al. 1999, Malinowski & uptake, host growth and fitness promotion.
Belesky 2000, Boddey et al. 2003, Loiret et al. This Hymenomycete colonizes the roots both
2004, Sandhiya et al. 2005, Firáková et al. inter- and intracellularly and forms coils or
2007). round bodies and branches in the cortex
without any colonization of the host stele
Role of Endophytes in Host Growth and (Verma et al. 1998, Varma et al. 1999). It
Nutrient Uptake seems that P. indica is capable of mobilizing
One of the most potential functions of plant unavailable P by excreting extracellular
endophytic fungi, especially root mycorrhizal phosphatases, as well as mediating uptake and
fungi is the facilitation of plant nutrient uptake translocation of labeled P via an energy
which in contrast leads to growth stimulation. dependent process (Singh et al. 2000). It is also
Improved nutrition and growth may have possible that P. indica is involved in N
42
Fig. 10 – Symbiotic development of biotrophic endophytes and pathogens a Once Arbuscular

mycorrhiza (AM) spores germinate and the germ tube approaches a root, apical dominance is
abandoned and the branching of hyphae is triggered by 5-deoxy-strigol (Akiyama et al. 2005).
Upon physical contact, the fungus forms an appressorium, which appears to induce the movement
of the plant nucleus towards the contact site b Cytoskeletal elements and the endoplasmic reticulum
form the pre-penetration apparatus along the axis of nuclear movement (Genre et al. 2005) c The
structure is entered by an infection hypha, from which d colonization of root cortex begins. Initial
infestation is accompanied by a balanced induction of plant defense genes. e When the fungus
finally reaches the inner cortex, it penetrates the cell wall and builds up a tree-like hyphal structure,
the arbuscule. Arbuscule-containing cells have specific cytoskeletal structures and accumulate
reactive oxygen species (ROS). While arbuscules develop and decease, the fungus spreads further
in the root and also colonizes the surrounding soil. There it takes up mineral nutrients, which are
transported into the root and exchanged for carbohydrates f Once a powdery mildew fungus
germinates, it forms an appressorium for host cell wall penetration g Appressoria seem to release
signals for the formation of membrane domains (yellow) into which host susceptibility factors and
defense factors are recruited (Bhat et al. 2005). In a compatible interaction, the host nucleus
transiently migrates to the site of attempted penetration (not shown) and some action filaments (red)
polarize toward this site h During penetration, host cell membrane is formed around the fungal
feeding structure (green), which is closely enveloped by actin filaments and led by a ring of action
around the growing tip (Opalski et al. 2005) i When the haustorium matures, a meshwork of cortical
actin is maintained around the haustorial neck, whereas actin polarisation resolves j Eventually, the
parasite establishes secondary haustoria and fulfils its lifecycle by producing a new generation of
conidia, Adapted from: (Kogel et al. 2006).
accumulation in the shoots of Nicotiana reductase activity, a key enzyme in nitrate

tobaccum and Arabidopsis thaliana. N content assimilation, in N. tobaccum and a similar 30%
in N. tobaccum was increased by 22%, increase in A. thaliana (Sherameti et al. 2005).
indicating a transfer of about 60% substrate N Seed production in N. tobaccum were also
into the plants. This N content increase was improved and increased with inoculation with
correlated with a 50% increase in nitrate P. indica as well as in Hordeum vulgare
43
(Barazani et al. 2005, Waller et al. 2005). This fungus Curvularia sp., survived high soil
endophyte appears to have a broad host range. temperature and water stress better than
It has been shown to colonize and enhance endophyte-free plants (Redman et al., 2002).
growth of, for example, Zea mays, Nicotiana Waller et al. (2005) reported the
tobaccum, Bacopa monniera, Artemisia annua, potential of Piriformospora indica to induce
Petroselinum crispum, Populus tremula, Oryza resistance to fungal diseases and tolerance to
sativa, Sorghum vulgare, Triticum sativum, salt stress in barley. The beneficial effect on
Glycine max, Cicer arientinum, Solanum the defense status was detected in distal leaves,
melongera, and terrestrial orchids like Dacty- demonstrating a systemic induction of
lorhiza purpurella, D. inacrnata, D. majalis tolerance and resistance by a root endophytic
and D. fuchsia (Singh et al. 2000, Varma et al. fungus. This systemically alternation was
1999). associated with increase of anti-oxidative
capacity due to an activation of the
Role of Endophytes in Production of Phyto- glutathioneascorbate cycle and results in an
Hormones overall increase in grain yield. Hence, such
Endophytes may enhance growth by symbioses are of great importance, since they
producing phytohormones without any appa- might help plants to adapt to global climate
rent facilitation of host nutrient uptake or change (Rodriguez et al. 2004).
stimulation of host nutrient metabolism. The
endophytic fungi may enhance biomass by Role of Endophytes on Photosynthetic
producing growth hormones or inducing the Capacity of Hosts:
host hormone production (Petrini 1991, Schulz Effects of endophytes on photosyn-
& Boyle 2005). The use of fungal culture thesis have been demonstrated, but they are not
extracts of endophytes to enhance plant always significant. For example, Colleto-
growth, indicate that soluble agents in culture trichum musae in banana decreased photo-
extracts may stimulate host growth similarly to chemical capacity compared to endophyte-free
the actively growing fungi, and this prove that plants (Pinto et al. 2000).
endophytic fungi produce phytohormones in
vitro as well as in vivo.
Role of Endophytes in Resistance against
For example, the mycelial extract of P. Pathogens and Herbivores (Biological
fortinii induced a similar increase in Larix Control)
decidua shoot and root biomass as did the Endophytic fungi can protect their host
fungus itself (Rommert et al. 2002), the growth plants from pathogens (Fig 11) and from pests
promotion was attributable to IAA as the (Arnold et al. 2003, Akello et al. 2007). The
fungus synthesized the hormone in vitro. A systemic and foliar endophytes can reduce
similar effect has also been observed with P. herbivory by producing alkaloids toxic to
indica. When a fungal filtrate (1% w/v) was insects and vertebrates (Schardl 2001).
added to maize seedlings three times a week Endophytic fungi are also capable of inducing
for 4 weeks, shoot biomass increase was resistance to diseases, and a many of
similar to that observed in inoculation experi- mechanisms have been proposed for this
ments with living cultures of the fungus resistance. The mechanisms of endophyte-
(Varma et al. 1999). induced resistance are related to the nutritional
status of the host, and to increase the fitness of
Role of Endophytes in Hosts Tolerance to plants by enhancing their tolerance to abiotic
Stress stress (Aguilar & Barea 1996, Redman et al.
Endophytes may help host plants to 2002, Bae et al. 2008).
tolerate and withstand environmental stress
such as drought, salts, and high temperatures Protection from Pathogens:
(Malinowski & Belesky 2000). In the herbal There are at least three primary
plant Dichanthelium lanuginosum, which lives mechanisms by which endophytes can improve
in areas where soil temperatures can reach 57 host resistance to pathogens (Mandyam &
°C, the presence of the endophytes may increa- Jumpponen 2005).
se plant fitness as plants with an endophytic
44
Fig. 11 – Endophytes and rhizobacteria are promoting plant growth, and accelerates
phytoremediation process though modulation of (a) plant growth promoting parameters, (b) by
providing plants with nutrients, and (c) controlling disease through the production of antifungal
metabolites, Adapted from (Ma et al. 2011).
The first mechanism is based on pathogen control may be related to ability of

competition between endophyte and pathogen endophytes to enhance the host to produce
on the same resources (Lockwood 1992). This phytoalexins, and/or biocidal compounds, or
is clear in a Fusarium oxysporum system. A ability of the endophyte itself to produce
non-pathogenic endophytic F. oxysporum Fo47 fumigants and other antimicrobial agents. As in
inhibits the pathogenic F. oxysporum f. sp. the case of Spilanthes calva when inoculated
radicis-lycopersici and reduces the root rot with Piriformospora indica, it produces a range
symptoms of tomato (Bolwerk et al. 2005). of antifungal compounds, as plants inoculated
Fo47 spores compete with the pathogen for the with P. indica produced extracts that were
same C source, thereby reducing nutrient inhibitory to soil-borne pathogens (F.
availability to the pathogen. Both of these oxysporum and Trichophyton mentagrophytes)
Fusarium strains exhibit similar colonization suggesting induction of antifungal chemical
strategies, so Fo47 can occupy and reduce the production in the host (Rai et al. 2002).
number of suitable sites for spore attachment The third possible mechanism is
and subsequent colonization resulting in fewer improving host resistance to pathogens by
symptomatic lesions. inducing host defense responses by localized
The second possible mechanism of endophytes. This mechanism is often
45
encountered in mycorrhizal plants where weak produce toxic alkaloids against insect and
resistance is induced locally or transiently vertebrate herbivores, and most of endophytic
during early mycorrhizal colonization. fungi may similarly play a role in protection of
Structural modifications and induction of hosts from pests and herbivores. Mandyam &
defense signaling can similarly result from Jumpponen (2005) suggested three possible
endophyte colonization (Koide & Schreiner mechanisms by which endophytes can improve
1992, Gianinazzi et al. 1996). resistance of host plants to herbivores and
An unidentified root-associated pests.
endophyte known as LtVB3 restricted the The first mechanism is based on overall
spread of Verticillium longissima in Brassica improvement of plant performance by endo-
campestris by forming mechanical barriers, phytes, which helps plants tolerate herbivory
cell wall appositions and thickenings and sustain damage without visible effects on
(Narisawa et al. 2004). As a result, external and productivity (Gehring & Whitham 2002).
internal pathogen symptoms were reduced by The second possible mechanism is the
over 80%. Narisawa et al. (1998) also observed alteration of plant nutritional chemistry both
inhibition of Plasmodiophora brassicae-caused qualitatively and quantitatively, by altering the
clubroot in B. campestris by about 5% by carbohydrate and nitrogen contents, C:N ratio
endophytes that were isolated; these endo- and phytosterol composition (Jones & Last
phytes were included Heteroconium chaeto- 1991, Bernays 1993, Schulz & Boyle 2005).
spira, Mortierella elongate, Westerdykella sp. The endophytes are capable of altering nutrient
as well as three unknown hyaline and levels and content in host plants which coupled
melanized species. They proposed that with alteration in carbohydrate metabolism,
superficial (M. elongata), cortical (hyaline and thus affect the host herbivore susceptibility.
DSE fungi, Westerdykella sp.), or superficial The third possible mechanism of host
and cortical (H. chaetospira) colonization herbivore resistance is the production of
created a mechanical barrier to the pathogens. feeding deterrents by the endophytes them-
It is likely that many tissue-penetrating selves. Toxic alkaloids are produced by foliar
endophytes may induce pathogen resistance endophytes of grasses (Clay 1990, Clay &
and in many cases, more than one of these Holah 1999). Non-pathogenic F. oxysporum, a
three mechanisms can act simultaneously. For common root endophyte in L. esculentum,
example, root colonization by Phialophora produces soluble toxic metabolites that are
graminicola can pre-emptively reduce the present in culture filtrates (Hallman & Sikora
growth of the pathogen Gaeumannomyces 1996). The filtrate has been shown to be toxic
graminis by competition for space and to Meloidogyne incognita, a root nematode.
resources. However, it can also form mecha- These toxic metabolites reduce nematode
nical barriers resulting from thickening of mobility, inactivate juveniles and are lethal
endodermis that inhibits colonization of the within a 24-h exposure. The effects of the
stele by the pathogen (Speakman & Lewis endophyte filtrates were reproducible in pot
1978, Deacon 1981). Similarly, any tissue experiments (Hallman & Sikora 1994), indica-
colonizing benign organism reduces available ting that the fungus also produces the
carbon to pathogens and can occupy likely metabolites in vivo. Mandyam & Jumpponen
colonization sites resulting in fewer possible (2005) suggest that extensive endophyte colo-
sites for pathogen penetration. nization may also prevent grazing on roots, as
many endophytes produce abundant melani-
Protection from Insects, Worm, Pests and zed structures, where melanin discourages
Herbivores microbial grazing (Bell & Wheeler 1986,
Some endophytes were found to have Griffith 1994). Periconia macrospinosa
negative effects on insects, inhibiting growth, extensively colonizes native grasses in the
survivorship or oviposition, especially mycorr- tallgrass prairie (Mandyam & Jumpponen
hizae and systemic and foliar Clavicipetalean 2005). Periconia spp. congeneric to those from
grass endophytes which are widely known to native prairies is known to produce chlorine
reduce herbivory. Clavicipitaceous fungi containing compounds that may have antibiotic
46
Fig. 12 – Importance of soil–plant–microbial interactions in bioremediation for the cleanup of metals and
organics (pesticides, solvents, explosives, crude oil, polyaromatic hydrocarbons), Adapted from (Ma et al.
2011).
properties. microorganisms for bioaccumulating heavy

metals and other pollutants from environment
Environmental Role of Endophytes or its enhancing plant growth and pollutant
Endophytes are found to play an uptake from soil by plant (Fig 12) through
important role in the ecological community, mobilization/ immobilization of pollutant (Ma
with the aim of decreasing the extent of et al. 2011).
environmental degradation, loss of biodiver- Endophytes may play indirect or direct
sity, and spoilage of land and water caused by role in phytoremediation process and degra-
excessive toxic organic insecticide, industrial dation of environmental toxins, indirectly
sewage, and poisonous gases. Biological through enhancing plant growth having ability
control using endophytes as a new efficient of phytoremediation and this accelerate phyto-
method is becoming widely used in remediation process (Fig 11), or directly
environmental remediation, and in killing through degradation and/or accumulating
insects or pathogens (Guo et al. 2008). pollutants by itself. Van Aken et al. (2004)
A novel application of endophytes in reported that new endophytic Methylobac-
the area of phytoremediation (plant assisted terium populum sp. nov., strain BJ001, was
removal of xenobiotics and heavy metals from involved in the degradation of energetic
soil) has been reported in many reviews (Ma et compounds such as 2,4,6-trinitrotoluene, hexa-
al. 2011). However, the success of hydro-1,3,5-trinitro-1,3,5-triazine, and hexa-
phytoremediation depends upon microbes and hydro-1,3,5-trimtro-1,3,5-triazine. Newman &
plant ability to tolerate and accumulate high Reynolds (2005) reported that plants inoculated
concentrations of pollutant, while yielding a with an engineered endophyte strain, had an
large biomass. Due to their importance for increased plant tolerance to toluene and
practical applications, pollutant-tolerant plant- decrease in the transpiration of toluene to the
microbe associations have been the objective of atmosphere.
particular attention due to the potential of Currently bio-insecticides are becoming
47
more widely used. Strobel & Daisy (2003) various biotechnological applications (Tomita
summarized several endophytic insecticides 2003).
naphthalene. Endophytes have a cryptic
existence and one of their main role in the Bio-Transformation Applications of
ecosystem are decomposers, as they are among Endophytes
the primary colonizers of dead plant tissues Biotransformation can be defined as the
(Kumaresan & Suryanarayanan 2002, Hyde & use of biological systems to produce chemical
Soytong 2008, Oses et al. 2008, Purahong & changes to compounds that are not in their
Hyde 2011). natural substrates (Borges et al. 2007). The
microbial growth, sustenance, and reproduction
Bio-Technological Applications of depends on the availability of a suitable form
Endophytes of reduced carbon source, used as chemical
Endophytes have high ability to energy, which under normal conditions of
produce various novel and known enzymes culture broth are the common sugars.
which could be used in various Microorganisms have high ability to adapt to
biotechnological applications like new environments and to metabolize various
environmental applications of degradation foreign substrates to carbon and nitrogen
enzymes, medical applications, and sources (Doble et al. 2004). A molecule can be
biotransformations of organic compounds with modified by transforming functional groups,
many advantage over other methods (Firáková with or without degradation of carbon skeleton.
et al. 2007, Pimentel et al. 2011, Sury et al. Such modifications result in the formation of
2012). novel and useful products not easily prepared
by chemical methods (Borges et al. 2009).
Enzymes Production by Endophytes Pimentel et al. (2011) reported many of
Endophytes usually produce the biotransformation processes by endophytes as
enzymes necessary for the colonization of plant following.
tissues. It has been demonstrated that most Biotransformation is a useful method
endophytes are able to utilize at least in vitro for production of novel compounds with
most plant nutrients and cell components. Most overcoming the problems associated with other
of investigated endophytes utilize xylan and chemical methods (Suresh et al. 2006). For this
pectin, show lipolytic activity and produce reason, the microbial biotransformation using
non-specific peroxidases and laccases, their enzymatic systems has received increased
chitinase and glucanase (Sieber et al. 1991; attention as a method for the conversion of
Leuchtmann et al. 1992, Moy et al. 2002, Li et lipids, monoterpenes, diterpenes, steroids,
al. 2004, Promputtha et al. 2011). Endophytes triterpenes, alkaloids, lignans, and some
may be a novel and good producers of xylanase synthetic chemicals, carrying out stereospecific
and the production of extracellular cellulase and stereoselective reactions for the production
and hemicellulases other than xylanases are of novel bioactive molecules with some
widespread but usually limited to organisms potential for pharmaceutical and food
derived from selected hosts or even host tissues industries (Borges et al. 2009, Figueiredo et al.
(Leuchtmann et al. 1992; Suto et al. 2002). 1996).
Thermostable amylolytic enzymes are being Endophytic microorganisms are able to
investigated to improve industrial processes for produce many enzymes (Firáková et al. 2007),
starch degradation. Streptosporangium sp. an so they could be used as biocatalysts in the
endophytic actinomycete isolated from leaves chemical transformation of natural products
of maize (Zea mays L.) showed glucoamylase and drugs, due to their ability to modify
production. The isolated enzyme exhibited chemical structures with a high degree of
thermostable properties (Stamford et al. 2002). stereospecificity and to produce known or
The ability of endophytes to produce various novel enzymes that facilitates the production of
enzymes in vivo and in vitro means that host compounds of interest. The biotransformation
supplies nutrients as well as habitats for of a tetrahydrofuran lignan, (-)-grandisin, by
endophyte colonization, and could be used for the endophytic fungus Phomopsis sp. from
48
Fig. 13 – Structure of some Bio-transformable Products
Viguiera arenaria is an example. The process recently using R- (+)-limonene, L-menthol, α-

led to the formation of a new compound named and β-pinene, and α-farnesene by diverse
dimethoxyphenyl)-5-methoxy-tetrahydrofuran microorganisms (Farooq et al. 2002a & b,
as 3,4-dimethyl-2-(4ʹ -hydroxy-3ʹ ,5ʹ- (Fig 13). Miyazawa et al. 2003, Krings et al. 2006,
This compound showed trypanocidal activity Maróstica & Pastore 2007, Bicas et al. 2008).
similar to its natural corresponding precursor Other endophytic microbes were studied for
against the causative agent of Chagas disease, the capability to biotransform natural products
the parasite Trypanosoma cruzi (Verza et al. like taxoids, alkaloids, pigment curcumim,
2009). betulinic, and betulonic acids (Zhang et al.
Zikmundová et al. (2002) reported 1998, Shibuya et al. 2003, Bastos et al. 2007,
isolation of endophytic fungus from the roots Simanjuntak et al. 2010).
and shoots of Aphelandra tetragona, capable of
transforming benzoxazinones, 2-benzoxazo- Pharmaceutical applications of Endophyte
linone (BOA) and 2-hydroxy-1,4-benzoxazin- Secondary Metabolites
3-one (HBOA), into a different series of Endophytes are the chemical
compounds. The use of endophytic fungi in the synthesizers inside plants (Owen & Hundley
stereoselective kinetic biotransformation of 2004). Many of them are capable of
“thioridazine (THD)”, a phenothiazine synthesizing bioactive compounds that can be
neuroleptic drug (Fig 13), was investigated. used as potential sources of pharmaceutical
Results showed that these microorganisms are leads. Endophytic fungi have been proven
able to biomimic mammalian metabolism via useful for novel drug discovery as suggested by
biotransformation reactions (Borges et al. the chemical diversity of their secondary
2007). Another study employed endophytic metabolites. Many endophytic fungi have been
fungus on the biotransformation of reported to produce novel antibacterial,
“propranolol (Prop)” to obtain 4-OH-Prop antifungal, antiviral, anti-inflammatory,
activemetabolite in enantiomerically pure form antitumor, and other compounds belonging to
(Borges et al. 2009). the alkaloids, steroid, flavenoid and terpenoids
Another interesting biotransformation derivatives and other structure types (Guo et al.
process is the use of endophytes in the 2008, Yu et al. 2010). Aly et al. (2011), De
biotransformation of terpenes for production of Souza et al. (2011) and Gutierrez et al. (2012)
novel compounds through enzymatic reactions summarized in amazing reviews the up-to-date
carried out by these microbes. “Terpenes” are and comprehensive information on compounds
large class of bioactive secondary metabolites from endophytes fungi from 1995 to 2011,
used in the fragrance and flavor industries, and together with the botany, phytochemistry,
have been extensively used in pharmacology and toxicology, and discussed
biotransformation process by microorganisms the possible trends and the scope for future
with focus on the discovery of novel flavor research of endophytes.
compounds and on the optimization of the The pharmaceutical and medical
process condition (Bicas et al. 2009). Microbial concerns of new drugs are the toxicity of these
transformations of terpenes were published prospective drugs to human tissues. Since the
49
Fig. 14 – Structure of Some Important Phytochemical Metabolites Produced by Endophytes
plant tissue where the endophytes exist is a Gentiana macrophylla is a traditional

eukaryotic system, it would appear that the Chinese medicinal plant. Its dominant active
secondary metabolites produced by the constituents are secoiridoids, mainly gentiopi-
endophytes may have reduced cell toxicity; crin (Fig14). The biological and pharmaco-
otherwise, death of the host tissue may occur. logical effects of its active principles include
Thus, the host itself has naturally served as a stomachic, choleretic, antihepatotoxic, antinfla-
selection system for microbes having bioactive mmatory, antifungal and antihistamine activi-
molecules with reduced toxicity toward higher ties. Endophytic fungal strain QJ18 were found
organisms (Strobel 2003). to produce the bioactive compound gentio-
Endophytes are universally present in picrin like its host plant G. macrophylla (Yin et
all of the world‟s higher plants, so it was al. 2009). Also, the medicinal plant Vinca
reasoned that plants might support certain minor contains the alkaloid vincamine (Fig14),
endophytic microorganisms that could synthe- which is used in the pharmaceutical industry as
size important phytochemicals of medicinal a cerebral stimulant and vasodilator. An extract
plants as well as the plant itself. Thus, if a from endophytic fungus (Vm-J2) were shown
microbial source of the drug was available, it to produce the same bioactive ingredient,
could eliminate the need to harvest and extract vincamine, as the host plant (Yin & Sun 2011).
the slow-growing and relatively rare trees. The Thus, endophyte production of natural metabo-
price for the drug would also be reduced, since lites may help to protect the natural resources
the drugs could be produced via fermentation and to satisfy the requirement of drugs via
in such the same way that penicillin is production of plant-derived pharmaceutical
fermented (Strobel 2003). leads by fermentation. Cui et al. (2012)
Many reports supported this idea. It supported this idea by isolation of ginkgolide B
began with the discovery of taxol producing from endophytic fungus Fusarium oxysporum
endophytes, the most potent anticancer drug, isolated from Ginkgo biloba.
from the culture of the endophytic fungi,
Taxomyces andreanae isolated from Taxus Anti Cancer Agents from Endophytes
brevifolia tree, and endophytic fungus Pestalo- Cancer is a disease characterized by
tiopsis microspora from medicinal plants unregulated cell proliferation, and leads to
Taxus wallichiana and bald cypress Taxodium spread of abnormal cells and uncontrolled
distichum (Stierle et al. 1993, Strobel et al. tissue growth (American Cancer Society 2009).
1993, Li et al. 1996, Strobel et al. 1996). Taxol It has been considered one of the major causes
has also been found in a number of different of death worldwide (about 13% of all deaths)
fungal endophytes such as Phyllosticta in 2004 (WHO 2009). There are some
spinarum, Bartalinia robillardoides, Pestalo- evidences that bioactive compounds produced
tiopsis terminaliae, Botryodiplodia theobro- by endophytes could be alternative approaches
mae. Also, other common endophytic genera for discovery of novel anticancer drugs
such as Alternaria, Aspergillus, Botrytis, (Firáková et al. 2007, Guo et al. 2008, Debbab
Cladosporium, Fusarium, and Mucor spp. have et al. 2011). Chandra (2012) reported many of
been reported as producers of taxol (Gangadevi endophytic fungi as novel sources of anticancer
& Muthumary 2008, Kumaran et al. 2008, lead molecules.
Gangadevi & Muthumary 2009, Pandi et al. The discovery of taxol-producing
2010, Zhao et al. 2010). endophytes opened the way for investigating
50
the anticancer properties of secondary Lignans show enormous structural and

metabolites of fungal endophytes. A selectively biological diversity, especially in cancer
cytotoxic quinone dimmer, torreyanic acid (Fig chemotherapy (Korkina et al. 2007). Puri et al.
15), an important anticancer agent, was isolated (2006) identified a novel fungal endophyte
from the endophytic fungus, Pestalotiopsis (Trametes hirsuta) that is able to produce aryl
microspora associated with a tree Torreya tetralin lignans “podophyllotoxins” (Fig 15).
taxifolia, and was shown 5 to 10 times more The lignans produced by the microorganism
potent cytotoxicity in cell lines that are are biologically active, and exhibit potent
sensitive to protein kinase C agonists and antioxidant, anticancer, and radioprotective
causes cell death by apoptosis (Lee et al. properties. Derivatives of podophyllotoxins are
1996). Recently, Mirjalili et al. (2012) currently used in cancer chemotherapy against
identified endophytic Stemphylium sedicola various cancer diseases. Also, phenylpro-
SBU-16 from the inner bark of Taxus baccata panoids have attracted much interest for
with Taxus taxadiene synthase (ts) gene, which medicinal applications mainly as anticancer
encodes the enzyme catalyzing the first and antioxidant agents, and were reported to be
committed step of taxol biosynthesis. produced by endophytes (Korkina et al. 2007).
The alkaloids are one of most potent The endophytic Penicillium brasilianum,
anticancer agents, usually found in endophytic isolated from root bark of Melia azedarach,
fungi. Wagenaar et al. (2000) reported promoted the biosynthesis of phenylpropanoid
identification of three novel cytochalasins amides (Fill et al. 2010).
alkaloid (Fig 15), possessing antitumor The endophytic fungus Curvularia
activity, from the endophytic genus lunata isolated from Niphates olemda, was
Rhinocladiella. Other important anticancer found to produce cytoskyrins (Fig 15), which
alkaloids are camptothecin (Fig 15) and its show antibacterial activity, and is considered as
derivatives, a potent antineoplastic agents; a potential anticancer agent (Brady et al. 2000,
camptothecin is used as a drug for treatment of Jadulco et al. 2002). Also, an endophytic
skin diseases in China (Guo et al. 2008). fungus Phoma medicaginis associated with
Camptothecin and 10-hydroxycamptothecin are medicinal plants Medicago sativa and Medi-
two important precursors for the synthesis of cago lupulina, yielded the antibiotic brefeldine
the clinically useful anticancer drugs, A (Fig 15), which also initiated apoptosis in
topotecan, and irinotecan (Uma et al. 2008). cancer cells (Weber et al. 2004b). Ergoflavin
An endophytic fungus isolated from the inner (Fig 15) is a dimeric xanthene, belonging to the
bark of the plant Nothapodytes foetida, was class of ergochromes, and was described as a
found to produce the anticancer lead compound novel anticancer agent isolated from an
camptothecin when grown in a synthetic liquid endophytic fungi growing in leaves of
medium (Sabouraud broth) under shake flask medicinal plant Mimusops elengi (Deshmukh
and bench scale fermentation conditions (Puri et al. 2009). Secalonic acid D also belonging to
et al. 2005). The anticancer compounds the ergochrome class, and known to have
Camptothecin and two analogues (9- potent anticancer activities, was isolated from
methoxycamptothecin and 10-hydroxycampto- the mangrove endophytic fungus and showed
thecin) were also obtained from the endophytic high cytotoxicity on HL60 and K562 cells by
fungus Fusarium solani isolated from inducing leukemia cell apoptosis (Zhang et al.
Camptotheca acuminata (Kusari et al. 2009b). 2009).
Several reports have described other Many of endophytes fungal metabolites
Camptothecin and/or analogues producing posses‟ strong cytotoxicty against different
endophytes (Amna et al. 2006, Rehman et al. cancer cell lines, which could be useful for dis-
2008, Liu et al. 2010b, Shweta et al. 2010). covery of lead anticancer drugs. Endophytic
Lignans are other kinds of anticancer unidentified fungus XG8D isolated from leaf
agents originated as secondary metabolites tissues of the mangrove plant Xylocarpus
through the shikimic acid pathway and display granatum, yielded a new nor-chamigrane
different biological activities that make them endoperoxide, merulin A (Fig 15), and new
interesting medically (Gordaliza et al. 2004). chamigrane endoperoxides, merulin C (Fig 15).
51
Fig. 15 – Structure of some Anticancer Agents Isolated from Endophytic Fungi
52
They showed cytotoxicity against BT474 cell The screening of crude extracts of
lines with IC50 values of 19.60 and 5.57μM, endophytic fungi of medicinal plants, showed
respectively, and activity against SW620 cell promising antitumor activity against different
lines with IC50 values of 19.05 and 14.57μM, cancer cell lines, as 13.4% of endophytic
respectively (Chokpaiboon et al. 2010). The extracts were cytotoxic on HL-60 cells and
chemical investigation of endophytic fungus 6.4% on KB cells (Huang et al. 2001). 9.2% of
Fusarium sp., isolated from stems of the other endophytic isolates exhibited antitumour
mangrove tree Kandelia candel, lead to activity on human gastric tumour cell line
isolation of new isoflavone,5-O-methyl-2`- BGC-823 (Li et al. 2005). Another study
methoxy-3`-methylalpinumisoflavone (Fig 15), showed that 3.3% of endophytic extracts
it inhibited the growth of HEp-2 and HepG2 display potent (IC50<0.01 μg/ml) cytotoxic
cancer cell lines with IC50 values of 4 and activity against the murine leukemic P388 cell
11μM, respectively (Huang et al. 2010). Isaka line and 1.7% against a human chronic myeloid
et al. (2010) isolated three new eremophilane- leukemia cell line K562 (Hazalin et al. 2009).
type sesquiterpenoids (Fig 15) from culture of Kumar et al. (2004) investigated the crude
endophytic fungus Xylaria sp., obtained from extracts of 343 endophytic fungi isolates and
the palm Licuala spinosa. The compounds detect thier in vitro suppressive activity on
exhibited moderate cytotoxic activities with phytohemaglutinin (PHA) stimulated
IC50 values ranging from 3.8 to 21.0μM against proliferation of human peripheral blood
human cancer cell lines (KB, MCF-7, and NCI- mononuclear cells (PBMC). In addition, Banu
H187) and nonmalignant Vero cells. & Kumar (2009) reported sixteen endophytic
Lu et al. (2010) investigated the fungal isolates exhibit antitumor activity in the
endophytic fungus Penicillium expansum, yeast cell-based assay.
isolated from roots of the mangrove plant The cytotoxicity effect of some fungal
Excoecaria agallocha, and found it to produce endophytes on mouse fibroblast cell line L-929
the new polyphenols, expansols A & B (Fig with their effects on nuclear morphology, cell
15). Expansols A exhibited moderate cytotoxic division, actin microfilaments and
activity against HL-60 cell line with an IC50 endomembrane system of PtK2 potoroo kidney
value of 15.7 μM, while expansols B showed cells revealed that some of the endophytes
pronounced activity with IC50 value 1.9 μM. produced metabolites that impair cell division
The endophytic fungal strain Allantophomopsis (Suryanarayanan et al. 2009). Among the
lycopodina, afforded the new natural product active endophytes is a genus Chaetomium that
allantopyrone A (Fig 15) and the known produced chaetoglobosins, which are
islandic acid-II methyl ester (Fig 15). Both cytochalasin analogs that inhibit actin
compounds exhibited cytotoxic activity against polymerization (Yahara et al. 1982) (Fig 16).
HL60 cells with IC50 values of 0.32 and 6.55 Chaetomium is a genus known to produce
μM, respectively, with observed internucleo- different types of cytotoxic metabolites
somal fragmentation when cells undergo including chaetomin, chaetoglobosins (Fig 15)
apoptosis, which indicate induction of apop- A, C, D, and G, chaetoquadrins, oxaspirodion,
tosis by this compounds (Shiono et al. 2010). chaetospiron, orsellides and chaetocyclinones
New depsidone-type metabolites, named paeci- (Lösgen et al. 2007). The common endophytic
loxocins A (Fig 15) was isolated from endo- fungus Chaetomium globosum, a lot of its
phytic Paecilomyces sp., isolated from the bark isolated compounds show anticancer activity,
of mangrove. Its showed significant cytotoxi- produced chaetoglobosin U (Fig 15) which
city against HepG2 cell line (IC50 2.69 μM), exhibited cytotoxic activity against the human
and it inhibited the growth of microbial nasopharyngeal epidermoid tumor KB cell line
pathogen Curvularia lunata and Candida albi- (Ding et al. 2006), also produced
cans as well (Wen et al. 2010). Finally, other globosuxanthone (Fig 15) which showed strong
compounds with anticancer properties isolated cytotoxicity against a seven human panel solid
from endophytic microbes were reported such tumor cell lines (Wijeratne et al. 2006), and
as phomoxanthones A-B, and photinides A-F produce cochliodinol (Fig 15) which proved to
(Isaka et al. 2001, Ding et al. 2009). be highly active against the cancer cell line
53
Control Treated
Fig. 16 – Effect of culture extract from endophytic Chaetomium sp. on mouse fibroblast cell line L-929.
Note cell enlargement, loss of actin fibres and failure of cell division after nuclear division. (Nucleus stained
with blue florescent dye and actin with red fluorescent dye). Adapted from: (Suryanarayanan et al. 2009).
(L5178Y mouse lymphoma cell line) with an a resistance mechanism to overcome

EC50 of 7.0 μg/ml (Debbab et al. 2009). pathogenic invasion by producing secondary
An endophytic Alternaria sp. metabolites bearing antimicrobial activity. It is
elaborated several solanapyrones (Fig 15) A, believed that screening for antimicrobial
D, E, F, and G, which are inhibitors of DNA compounds from endophytes is a promising
polymerases (Mizushina et al. 2002). way to overcome the increasing threat of drug
Endophytic Nigrospora oryzae produced resistant microbes of human and plant
aphidicolin and several of its derivatives, pathogen (Tan & Zou 2001, Yu et al. 2010).
nigrosporolide, phomalactone, bostrycin and The antimicrobial compounds can be used not
epoxyexserohilone. Aphidicolin is a tetracyclic only as drugs by humankind but also as food
diterpene-tetraol and an inhibitor of nuclear preservatives in the control of food spoilage
DNA synthesis in eukaryotes, it inhibited DNA and food-borne diseases, a serious concern in
synthesis by interfering with DNA polymerase the world food chain (Liu et al. 2008).
α enzyme, also this metabolite reported to The screening of endophytic fungi
inhibit the S phase of the cell cycle (Ikegami et crude extracts for their antimicrobial activity
al. 1979, Spadari et al. 1982). Furthermore, indicates that they may possess the steadiness
endophytic Fusarium sp. was shown to antimicrobial activity against tested pathogens
produce apicidin which is a histone deacetylase such as Staphylococcus aureus, Bacillus
inhibitor that inhibits cell division, and subtilis, Saccharomyces cerevisiae and Alter-
enniatins which are known to function as naria sp., etc. Li et al. (2005) reported 30% of
inhibitors of the yeast transporter protein Pdr5p tested isolates exhibited antifungal activity,
(Han et al. 2000, Hiraga et al. 2005). From the also antimicrobial activity was demonstrated
previous, certain endophytic genera such as for 8%-92% of endophytic extracts in other
Alternaria, Chaetomium, Colletotrichum, studies (Banu & Kumar 2009, Hazalin et al.
Curvularia, Nigrospora and Xylaria produce a 2009, Tong et al. 2011).
larger number of cytotoxic compounds that Cryptocin (Fig 17.a) and cryptocandin
could be used in discovery of new anticancer (Fig 17.b) are antifungal metabolites obtained
agents (Suryanarayanan et al. 2009). from the endophytic fungus Cryptosporiopsis
cf. quercina. Cryptocandin demonstrated
Antimicrobial Agents from Endophytes excellent antifungal activity against some
Antimicrobial metabolites (Antibiotics) important human fungal pathogens, including
can be defined as low-molecular-weight Candida albicans and Trichophyton spp., and
organic compounds made by microorganisms against a number of plant pathogenic fungi,
that are active at low concentrations against including Sclerotinia sclerotiorum and Botrytis
other microorganisms, not required for its cinerea. Cryptocandin and its related com-
growth, produced as an adaptation for specific pounds are currently being considered for use
functions in nature, and are the most bioactive against a number of fungi causing diseases of
natural products isolated from endophytes the skin and nails (Strobel & Daisy 2003).
(Demain 1981, Strobel & Daisy 2003, Guo et Cryptocin however possesses potent activity
al. 2008). Endophytes are believed to carry out against plant pathogens only, especially against
54
Pyricularia oryzae, the causal organism of one and aurasperone A (Fig 17.a) from Aspergillus
of the worst plant diseases in the world, with niger IFB-E003, an endophyte in Cyndon
minimum inhibitory concentration 0.39μg/ml dactylon. The four metabolites exhibited
(Strobel et al. 1999b, Li et al. 2000). The growth inhibitions against the pathogenic
endophytic fungus Pestalotiopsis microspora microbes with minimal inhibitory concentra-
was found to produce number of antifungal tions (MICs) ranging in between 1.9 and 31.2
metabolites, like ambuic acid, pestaloside, and µg/ml. Another novel antibiotic-phomol was
pestalotiopsins A and B (Fig 17.a). They isolated from fermentations of an endophytic
showed activity against many of pathogenic fungus Phomopsis species, another two
fungi, while pestaloside possess also antimicrobial agents cytosporone B and C (Fig
phytotoxic properties. An endophytic fungi 17.b) were isolated, from the same genus
Pestalotiopsis jesteri and Pestalotiopsis adusta Phomopsis sp.; they inhibited two fungi
were found to synthesized jesterone (Fig 17.a) Candida albicans and F. oxysporum with the
and Pestalachlorides A respectively, which MIC value ranging from 32 to 64 mg/ml.
exhibit antifungal activity against a variety of Investigation of endophytic Phomopsis cassia,
plant pathogenic fungi (Li et al. 2008a). ethyl 2,4-dihydroxy-5,6-dimethylbenzoate and
Pestalachlorides A was proven to display phomopsilactone displayed strong antifungal
significant antifungal activity against three activity against two phytopathogenic fungi,
plant pathogenic fungi, Fusarium culmorum, Cladosporium cladosporioides, and C.
Gibberella zeae, and Verticillium albo-atrum sphaerospermum (Weber et al. 2004, Silva et
(Lee et al. 1995b, Pulici et al. 1996, Li et al. al. 2005, Huang et al. 2008b).
2001, Li & Strobel 2001, Li et al. 2008a). Chemical investigations of corn
Lu et al. (2000) isolated three endophyte Acremonium zeae led to the
metabolites (Fig 17.a) from the culture of discovery of two antibiotics pyrrocidines A and
endophytic fungus Colletotrichum sp., residing B (Fig 17.b), which displayed significant
in the medicinal Artemisia annua. These antifungal activity against Aspergillus flavus
compounds were shown to have not only have and Fusarium verticillioides (Wicklow et al.
activity against human-pathogenic fungi and 2005). More than 50% of endophytic fungal
bacteria but also be fungistatic to plant- strains residing in Quercus variabilis possessed
pathogenic fungi. Krohn et al. (2002) reported growth inhibition against at least one
fusidikactones (Fig 17.a) with antifungal pathogenic fungi or bacteria. Cladosporium
activity from endophytic Fusidium species. sp., displaying the most active antifungal
Preaustinoid A, B (Fig 17.a) isolated from activity, was investigated and found to produce
Penicillium sp., exhibited moderate bacterio- a secondary metabolite known as brefeldin A
static effect on Escherichia coli, Staphylo- with antibiotic activity (Wang et al. 2007). The
coccus aureus, Pseudomonas aeruginosa, antimicrobial agents Hypericin (Fig 17.a) and
Bacillus sp. (Dos Santos & Rodrigues-Fo Emodin were produced by Hypericum
2003). Kim et al. (2004) isolated antibacterial- perforatum. Both compounds possessed
periconicins A and B (Fig 17.b) from antimicrobial activity against several bacteria
endophytic fungus Periconia sp. isolated from and fungi, including Staphylococcus aureus
host plant Taxus cuspidate. Among metabolites ssp. aureus, Klebsiella pneumoniae ssp.
produced by the endophytic fungus Aspergillus ozaenae, Pseudomonas aeruginosa, Salmonella
fumigatus CY018 asperfumoid (Fig 17.a), enterica ssp. Enteric, and Escherichia coli, and
fumigaclavine C, fumitremorgin C, physcion, fungal and candidal pathogens Aspergillus
and helvolic acid were shown to inhibit niger and C. albicans (Kusari et al. 2008).
Candida albicans (Liu et al. 2004). Chaetoglobosins A and C with antifungal
Investigation of endophytic fungus activities were characterized from the culture
Rhizoctonia sp. yielded rhizoctonic acid (Fig of an endophytic Chaetomium globosum
17.a) with anti-helicobacter pylori activity, the isolated from leaves of Ginkgo biloba. In agar
causative bacteria of peptic ulcer (Ma et al. diffusion method, these two metabolites were
2004). Song et al. (2004) reported isolation of shown antimicrobial activity against Mucor
rubrofusarin B, fonsecinone A, asperpyrone B, miehei (Qin et al. 2009).
55
The endophytic genus Xylaria was endophytes. Muscodor is a novel endophytic

investigated as producers of many antifungal fungal genus that produces bioactive volatile
agents; species produce griseofulvin (Fig 17.a) organic compounds (VOCs). This fungus, as
which is used for the treatment of human and well as its VOCs, has enormous potential for
veterinary animals mycotic diseases. Sordaricin uses in agriculture, industry and medicine.
and multiplolides had antifungal activity Endophytic Muscodor albus and the most
against Candida albicans,7-amino-4- recent discovered Muscodor crispans produce
methylcoumarin showed broad-spectrum a mixture of VOCs that act synergistically to
inhibitory activity against several food-borne kill a wide variety of plant and human
and food spoilage microorganisms. It was pathogenic fungi and bacteria. It is also
suggested for use as natural preservatives in effective against nematodes and certain insects.
food. In vitro and in vivo antifungal activity of This mixture of gases consists primarily of
endophyte-produced griseofulvin against plant various alcohols, acids, esters, ketones and
pathogenic fungi were effective for controlling lipids (Fig 17.a). Artificial mixtures of the
effectively the development of various food VOCs mimic the biological effects of the
crops diseases (Boonphong et al. 2001, Cafěu fungal VOCs when tested against a wide range
et al. 2005, Park et al. 2005, Liu et al. 2008, of fungal and bacterial pathogens. Potential
Pongcharoen et al. 2008). applications for „„mycofumigation‟‟ by this
Curvularide B (Fig 17.a) was isolated genus are currently used for treating various
from the endophyte Curvularia geniculata and plant diseases, buildings, soils, agricultural
showed antifungal activity with increase in produce and human wastes. Another promising
inhibition zone in the presence of fluconazole option includes its use to replace methyl
(example of currently used azol drug), which bromide fumigation as a means to control soil-
indicated the synergistic effect of both drugs borne plant diseases (Strobel 2006 a & b,
against Candida albicans. The minimum Strobel 2011).
inhibitory concentrations (MIC) values that Recently, Tuberculosis inhibitors were
produced no visible growth (MIC-0) for found among endophytes, some of endophytes
fluconazole and curvularide B were 26.1 and were found to inhibit Mycobacterium aurum
782.8μM, respectively. While in combination, and Mycobacterium tuberculosis, the causative
the MIC-0 values decreased to 3.2 and 48.9μM, organisms of tuberculosis. Rukachaisirikul et
respectively. Curvularide B did not exhibit al. (2008) isolated phomoenamide (Fig 17.b)
cytotoxicity towards ten human cancer cell which exhibited in vitro antimycobacterial
lines even at a concentration of 50μg/ml, which activity against M. tuberculosis H37Ra. The
indicates positive results for using it to improve screening of endophytic extracts, lead to
activity of azol antifungal drugs (Chomcheon isolation of endophytic isolate from Vaccinium
et al. 2010). The mangrove derived endophytic myrtillus which show MIC 8 μg/ml against M.
fungus Talaromyces sp. produced the antimi- aurum, and endophytes from Calluna vulgaris,
crobial metabolites (7-epiaustdiol, stemphy- Empetrum nigrum, Vaccinium vitis-idaea and
perylenol and secalonic acid A). 7-epiaustdiol V. myrtillus which show 90 to 96% inhibition
(Fig 17.a) displayed significant inhibitory at 100 μg/ml against M. tuberculosis (Gordien
activity against Pseudomonas aeruginosa, a et al. 2010). Chemical analysis of mangrove
multidrug resistant opportunistic pathogen, endophytes Fusarium sp. led to the isolation of
with MIC value of 26.48μM. Stemphy- fusaric acid which used for synthesis a variety
perylenol (Fig 17.a) inhibited Sarcina of metal complexes of fusaric acid. Antimyco-
ventriculi with MIC value of 8.86μM, which is bacterial assays showed that Cadmium (II) and
lower than that of ampicillin (35.81μM), while Copper (II) complexes exhibited potent
secalonic acid A (Fig 17.a) exhibited high inhibitory activity against M. bovis BCG strain
activities against all tested organisms. with MIC 4 μg/mL and M. tuberculosis
Furthermore, the three compounds showed H37Rv strain with MIC 10 μg/ml (Pan et al.
moderate to strong cytotoxicity against KB and 2011). Verma et al. (2011) reported the
KBv200 cell lines (Liu et al. 2010c). endophytic fungus Periconia sp. produces
Fumigants are produced by many of piperine with strong antimycobacterial activity
56
Fig. 17a – Structure of Some Antimicrobial Metabolites from Endophyets.
against M. tuberculosis and M. smegmetis with that there is a great opportunity to utilize
MIC 1.74 and 2.62 μg/ ml, respectively. endophytes as a new source for production of
Yu et al. (2010) published a remarkable reliable and novel antimicrobial agents. They
review of antimicrobial metabolites (Fig 17b) also stated that this could be a promising way
isolated from endophytes, and belong to to solve the problem of microbial resistance to
several classes, including: alkaloids, peptides, commonly used drugs and meet the emergency
steroids, terpenoids, phenols, quinines, and demand of discovering highly effective, low
flavonoids. They concluded that as so many toxicity, and environmentally friendly antibio-
antimicrobial compounds were isolated from tics, which may be used as clinically effective
endophytes which only occupied a small antibiotics in future.
portion of total endophyte species, it is obvious
57
Fig. 17b – Structure of Some Antimicrobial Metabolites from Endophytes that reported in Yu et al.
(2010).
AntiOxidant Agents from Endophytes variety of pathological effects. For instance,

The importance of compounds bearing DNA damages, carcinogenesis, and cellular
antioxidant activity lies in the fact that they are degeneration (Huang et al. 2007, Seifried et al.
highly effective against damage caused by 2007). Antioxidants have been considered
reactive oxygen species (ROSs) and oxygen- promising therapy for prevention and treatment
derived free radicals, which contribute to a of ROS-linked diseases as cancer,
58
Fig. 18 – Structure of Some Antioxidant Compounds Isolated from Endophytic Fungi
cardiovascular disease, atherosclerosis, hyper- Huang et al. (2007) investigated the

tension, ischemia/reperfusion injury, diabetes antioxidant capacities of endophytic fungal
mellitus, neurodegenerative diseases (Alzhei- cultures of medicinal Chinese plants and its
mer and Parkinson diseases), rheumatoid correlation to their total phenolic contents.
arthritis, and ageing (Valko et al. 2007). They suggested that the phenolic content were
Fungal endophytes associated with the major antioxidant constituents of the
higher plants appear to be a good source of endophytes (Huang et al. 2008a). The methanol
novel antioxidants as well as plants. Pestacin extract of an endophyte Xylaria sp. isolated
and isopestacin (Fig 18) are compounds from the medicinal plant Ginkgo biloba
displaying potent antioxidant activity and have exhibited strong antioxidant capacity due to the
been obtained from culture of endophytic presence of “phenolics” and “flavonoids”
fungus Pestalotiopsis microspora isolated from among identified compounds (Liu et al. 2007).
host plant Terminalia morobensis. Besides Recently, the endophytic Corynespora
antioxidant activity, pestacin and isopestacin cassiicola was found to produce potent
also show antimycotic and antifungal activities, antioxidant compounds corynesidones A and
respectively. Isopestacin antioxidant activity B, and corynether A, together with a known
was attributed to its structural similarity to the diaryl ether (LL-V125α) (Fig 18), as revealed
flavonoids, it is able to scavenge superoxide by oxygen radical absorbance capacity
and hydroxyl free radicals in solution. The (ORAC) assay with units ranging between 4.3-
proposed antioxidant activity of pestacin arises 5.9. Corynesidone B could also scavenge 2,2-
primarily via cleavage of an unusually reactive diphenyl-1-picrylhydrazyl (DPPH) free radi-
C-H bond and, to a lesser extent, through OH cals with an IC50 22.4 µM, at the same activity
abstraction; it is believed to have antioxidant as that of ascorbic acid. Beside antioxidant
activity 11 times greater than trolox, a vitamin activity of corynesidone A, its exhibit
E derivative (Strobel et al. 2002, Harper et al. aromatase inhibitory activity with an IC50 value
2003). of 5.30 µM; this activity magnitude is
The endophytic Cephalosporium sp. comparable to the first generation aromatase
IFB-E001 and Microsphaeropsis olivacea were inhibitor drug, aminoglutethimide. Both anti-
isolated from host plants Trachelospermum aromatase and antioxidant activities of
jasminoides and Pilgerodendron uviferum corynesidone A are interesting functions
respectively; both produced a phenolic because this dual biological activity may be
metabolite graphislactone A (Fig18), which useful for cancer chemoprevention, particularly
displayed potent in vitro antioxidant and free for breast cancer (Chomcheon et al. 2009).
radical-scavenging activity stronger than the Also, the endophyte fungus Phyllosticta sp.
standards, butylated hydroxytoluene (BHT) isolated from Guazuma tomentosa was also
and ascorbic acid (Hormazabal et al. 2005, found to exhibit strong antioxidant activity
Song et al. 2005). (Srinivasan et al. 2010). Zeng et al. (2011)
59
reported many of endophytic fungi as potential cancer and viral infections, like etoposide,
novel source of natural antioxidants from teniposide, and etopophos phosphate.
medicinal plant Scapania verrucosa. Podophyllotoxin was found to produced by
many endophytes: Trametes hirsute,
Antiviral Activities of Endophytic Fungi Aspergillus fumigates, Phialocephala fortinii,
Many reports demonstrated the and Fusarium oxysporum ( Eyberger et al.
importance of endophytic fungi in production 2006, Puri et al. 2006, Kour et al. 2008, Kusari
of antiviral agents, such as, cytonic acids A and et al. 2009a).
B, novel human cytomegalovirus (hCMV) Arunpanichlert et al. (2010)
protease inhibitors, which had been isolated investigated the secondary metabolites of
from solid-state fermentation of the endophytic endophytic fungus Penicillium sclerotiorum,
fungus Cytonaema sp., )Guo et al. 2000). and isolated the known compound (+)-
Investigation of endophytes associated with Sclerotiorin. (+)-Sclerotiorin (Fig 19) was
leaves of Quercus coccifera lead to isolation of evaluated for its inhibitory effect on human
the endophyte with the ability to synthesize immunodeficiency virus HIV-1 integrase and
hinnuliquinone, a potent inhibitor of human protease and for antifungal activity, and found
immunodeficiency virus type 1 (HIV-1) to exhibit anti-HIV-1 integrase and protease
protease (Singh et al. 2004). activities with IC50 values of 45.88 and
Endophytic isolates (582) with 360 198.41μM, respectively, and showed weak
morphologically distinct fungi were obtained anti-fungal activity against Candida albicans
from 81 Thai medicinal plant species. Extracts and Cryptococcus neoformans with MIC
of 92 isolates could inhibit Mycobacterium values of 202.53 and 101.26 μM, respectively.
tuberculosis, while 6 extracts inhibited The endophyte Phomopsis sp., isolated
Plasmodium falciparum, and strong anti-viral from Musa acuminata, was found to produce
activity against Herpes simplex virus type 1 hexaketide γ-lactones. Oblongolides Z, and 2-
was observed in 40 isolates (Wiyakrutta et al. deoxy-4α-hydroxyoblongolide X (Fig 19)
2004). Mellisol and 1,8-dihydroxynaphthol 1- showed anti-herpes simplex virus type 1 (HSV-
O-a-glucopyranoside were isolated from 1) activity IC50 values of 14 μM and 76 μM,
endophytic fungus Xylaria mellisii, which respectively. Oblongolides Z exhibited
possess activity against herpes simplex virus- comparable cytotoxic activity against KB, BC,
type 1 (Pittayakhajonwut et al. 2005). NCI-H187, and nonmalignant Vero cell lines
Florke et al. (2006) reported anti- with IC50 values of 37, 26, 32, and 60μM,
hepatitis C virus (HCV) activity of dihydroiso- respectively (Bunyapaiboonsri et al. 2010).
coumarin (R)-(-)-mellein (Fig 19). It inhibits New chlorinated pupukeananes possessing a
HCV protease with an IC50 value of 35 mM. unique spiroketal peroxide skeleton, named
This compound had been isolated from a chloropupukeanolides A (Fig 19), were
number of endophytic fungi, such as Pezicula isolated from endophytic Pestalotiopsis fici.
livida, Plectophomella sp., and Cryptosporiop- This compound was found to inhibit HIV-1
sis malicoticis (Krohn et al. 1997). Pullularins replication in vitro in C8166 cells with an IC50
A (Fig 19), which had been isolated from ethyl value of 6.9 μM, and showed cytotoxicity
acetate extract of endophytic fungus Pullularia against human cancer cell lines HeLa, MCF-7
sp., was also shown to have antiviral activity and MDA-MB-231 with IC50 values of 16.9,
against herpes simplex virus type 1(HSV-1) 15.5 and 15.9μM, respectively (Liu et al.
with IC50 3.3 mg/ml (Isaka et al. 2007). Pesta- 2010a).
lotheol C (Fig 19), which was isolated from the Zhang et al. (2011) reported isolation
endophyte Pestalotiopsis theae, was found to and structure elucidation of Emerimidine A,
have anti-HIV properties (Li et al. 2008b). and B (Fig 19) from culture of endophytic
The aryl tetralin lignans, such as fungus Emericella sp., both of them showed
podophyllotoxin and its analogs showed moderate inhibition to Influenza virus H1 N1
antiviral and cytotoxicity activities and used as with IC50 values of 42.07 mg/ml and 62.05
the precursor for many drugs for treatment mg/ml respectively.
60
Fig. 19 – Structure of Antiviral Compounds isolated from some Endophytic Fungi
Other Biological Activities of Endophytic endophytic Pestalotiopsis leucothes isolated

Fungi from Trypterygium wilfordii was found to
Endophytic fungi are also known as produce compounds which have variable
producers of many other metabolites of effects on T- and B-cells and monocyte, these
biological interest, such as anti-inflammatory, compounds may represent a new source of
anti-diabetic, anti-malarial and immunesup- immunomodulatory agents or for treatment of
pressant agents, as well as insecticidal and anti- human immune mediated diseases (Kumar et
nematodes agents. al. 2005). A new compound named Collutelin
Immunosuppressive drugs are used to A, has been isolated from endophytic
prevent allograft rejection in organ Colletotrichum dematium and was shown to
transplantation, and could be used to treat exhibit strong immunosuppressive activity as it
autoimmune diseases such as rheumatoid inhibited CD4 (+) Tcell activation of
arthritis and insulin-dependent diabetes. Lee et Interleukin 2 production (Ren et al. 2008).
al. (1995a) reported endophytic Fusarium Gliocladicillins A and B were reported as
subglutinans can produce compounds (Subglu- effective antitumor agents in vitro and in vivo,
tinol A and B) that can influence the immune since they induced tumor cell apoptosis and
system of animals. Subglutinol A (Fig 20) and showed significant inhibition on proliferation
B are noncytotoxic diterpene pyrones; both of of melanoma B16 cells implanted into
compounds have IC50 values of 0.1 μM and immunodeficient mice (Chen et al. 2009).
were roughly as potent as the immunosup- Zhang et al. (1999) investigated the
pressant drug cyclosporin A. The lack of anti-diabetic activity of endophytic fungi by
toxicity associated with subglutinols A and B isolation of nonpeptidal L-783, 281 from an
suggests that they could be use as endophytic Pseudomassaria sp., this
immunosuppressant agents. Recently, the compound was found to act as insulin, with
61
advance that it is not destroyed in the digestive and 1-chloro-2,4-dihydroxy-5-methoxy-7-

tract and may be given orally. Oral methylanthraquinone” (Fig 20) have been
administration of L-783,281 in two mouse isolated from culture of Penicillium sp., an
models of diabetes resulted in significant endophyte isolated from Egyptian plant
lowering of blood glucose levels, these results Limonium tubiflorum, with IC50 values ranging
may lead to a new therapeutic agent for from 1.6 to 10.1 µM for isolated compounds
diabetes. Insulin-mimetic compound demethyl (Aly et al. 2011).
asterriquinone B-1 (Fig 20) has been isolated Xanthine oxidase (XO) is a key enzyme
from culture of endophytic Pseudomassaria sp. that catalyzes the oxidation of xanthine and
(Salituro et al. 2001, Strobel 2002). hypoxanthine into uric acid, and plays a vital
Many reports indicated that endophytic role in hyperuricemia and gout. Allopurinol is
fungi are capable of producting of anti- a clinically used to inhibit XO in the treatment
inflammatory compounds, such as phomol and of gout, but it has unwanted side effects. Many
mevinic acid (Fig 20), which had been isolated endophytes were reported to produce
from culture of the endophytic fungus compounds exhibit strong xanthine oxidase
Phomopsis. (Weber et al. 2004a). Both inhibitory activity, like Alternariol (Fig 20)
compounds showed strong anti-inflammatory which has been isolated from endophytic
activity. Phenylpropanoids compounds were Alternaria brassicicola, with IC50 15.5 µM
reported to be isolated from endophytes; they inhibitory activity. Compounds from
have received more interest for medicinal endophytic Aspergillus niger, named
applications as they have multifold activities, rubrofusarin B, aurasperone A (Fig 20), also
such as anticancer, antioxidant, antimicrobial, showed strong co-inhibition of xantin oxidase,
anti-inflammatory and immunosuppressive cytotoxicity to colon cancer cell lines and was
properties (Korkina 2007). an inhibitor of some microbial pathogens
Wang et al. (2010) reported isolation of (Song et al. 2004, Gu 2009).
four compounds (Epicoccins M & R, Ent- Yang et al. (2010) investigated an
epicoccin G, and Diketopiperazine) that endophytic Phomopsis sp., isolated from the
exhibited potent anti-inflammatory activities stem of the mangrove tree Excoecaria
from cultures of endophytic Epicoccum agallocha and reported isolation of Phomopsis-
nigrum. The compounds were found to inhibit H76 A, B and C from culture filtrate.
the platelet activating factor-induced release of Phomopsis-H76 A (Fig 20) was found to
β-glucuronidase from rat polymorphonuclear induce formation of ectopic vessels in the
leukocytes in vitro with IC50 values of 4.16, subintestinal vessel plexus (SIV), whereas
4.95, 3.07 and 1.98μM, respectively, in Phomopsis-H76 C (Fig 20) was found to
comparison to the positive control ginkgolide inhibit blood vessel formation.
B which show IC50 2.35μM values. Isaka et al. (2007) reported isolation of
Recent studies showed that chronic pullularin A, B and C (Fig 19) from culture of
inflammation might be contributed to endophytic fungus Pullularia sp. These
inflammation-associated cancer. Nuclear factor compounds showed strong anti-malarial
kappa B (NF-κB) is known to regulate diverse activity as they inhibit activity of Plasmodium
cellular processes including inflammation, falciparum K1 (K1, refer to multi-drug
immune response, differentiation, proliferation, resistant strain) with IC50 3.6, 3.3, and 9.8
apoptosis and cancer. The role of NF-κB µg/ml values respectively. Romero et al.
activation pathway in acute inflammation and (2008) isolated lactones from endophytic
cell-survival, as well as its sustained activation Xylaria sp., with potential activity against
in several cancer cases has been reported. Plasmodium falciparum, which could use as
Linking inflammation to tumor promotion and leads for anti-malarial drugs. Butyrolactone V
progression, so interfering NF-κB activation, compound (Fig 20) has also been isolated from
and targeting NF-κB in chronic inflammatory endophytic Aspergillus terreus, showing anti-
diseases could reduce cancer incidence. NF-κB malarial activity with an IC50 17.95μM
inhibitors “11β-methoxycurvularin, 11α- (Haritakun et al. 2010). Isaka et al. (2010) also
methoxycurvularin, Trans-dehydrocurvularin, isolated sesquiterpenoids compounds (Fig 15)
62
Fig. 20 – Structure of some Endophytic metabolites showing variable biological activities.
eremophilane-type, with anti-malarial activity janthinellum from fruits of Melia azedarach,

with IC50 values ranging between 8.1-13.0 μM, was found to show 100% anti-parasitic activity
from endophytic Xylaria. against Leishmania sp. (Marinho et al. 2005).
The polyketide Citrinin (Fig 20), Aly et al. (2011) investigated the antitrypano-
produced by endophytic fungus Penicillium somal activity of endophytic fungi by isolation
63
of 11β-methoxycurvularin, 11α-methoxycur- chaetomium, towards the cotton aphis (Aphis

vularin, 5-chloro-6,8,10-trihydroxy-1-methoxy gossypii).
-3-methyl-9(10H)-anthracenone, and trichodi-
merol (Fig 20) from endophytic Penicillium sp. Conclusion
These compounds showed inhibitory activity Isolation of endophytic fungi from
against parasitic protozoan Trypanosoma medicinal and other plants may result in
brucei, the causative agent of trypanosomiasis methods to produce biologically active agents
(sleeping sickness), with IC50 4.96, 9.68, 9.75, for biological utilization on a large commercial
and 6.29 µM, respectively. scale as they are easily cultured in laboratory
A number of endophytic fungi could be and fermentor instead of harvesting plants and
classified as entomopathogenic and nemato- affecting the environmental biodiversity.
phagous fungi and considered as biocontrol
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Current Research in Environmental & Applied Mycology Doi 10.

Biology of Endophytic Fungi

Selim KA1,*, El-Beih AA1, AbdEl-Rahman TM2 and El-Diwany AI 1

Key words – Biological Roles – Ecology – Endophytic Fungi – Identification – Isolation –

Introduction actinomycetes, and fungi). The discovery of

Fig. 2 – Structure of some biological active microbial metabolites

Fig. 3 – Taxol, anticancer drug produced by many endophytic fungi.

Fig. 4 – Oocydin A, antifungal agent isolateded from Serratia marcescens.

Discovery the Importance of Endophytic 1996). Furthermore, several other P.

Isolation of Endophytic Fungi flasks over a three months period to promote

defenses. of the endophyte would also result in a change

Roles of Endophytes on Host-Plants positive indirect effects on the other well-

Fig. 10 – Symbiotic development of biotrophic endophytes and pathogens a Once Arbuscular

accumulation in the shoots of Nicotiana reductase activity, a key enzyme in nitrate

The first mechanism is based on pathogen control may be related to ability of

properties. microorganisms for bioaccumulating heavy

Fig. 13 – Structure of some Bio-transformable Products

Viguiera arenaria is an example. The process recently using R- (+)-limonene, L-menthol, α-

Fig. 14 – Structure of Some Important Phytochemical Metabolites Produced by Endophytes

plant tissue where the endophytes exist is a Gentiana macrophylla is a traditional

the anticancer properties of secondary Lignans show enormous structural and

Fig. 15 – Structure of some Anticancer Agents Isolated from Endophytic Fungi

(L5178Y mouse lymphoma cell line) with an a resistance mechanism to overcome

The endophytic genus Xylaria was endophytes. Muscodor is a novel endophytic

Fig. 17a – Structure of Some Antimicrobial Metabolites from Endophyets.

AntiOxidant Agents from Endophytes variety of pathological effects. For instance,

Fig. 18 – Structure of Some Antioxidant Compounds Isolated from Endophytic Fungi

cardiovascular disease, atherosclerosis, hyper- Huang et al. (2007) investigated the

Fig. 19 – Structure of Antiviral Compounds isolated from some Endophytic Fungi

Other Biological Activities of Endophytic endophytic Pestalotiopsis leucothes isolated

advance that it is not destroyed in the digestive and 1-chloro-2,4-dihydroxy-5-methoxy-7-

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