fungal biology reviews 23 (2009) 9–19

journal homepage: www.elsevier.com/locate/fbr

Review

Fungal endophytes and bioprospecting

T. S. SURYANARAYANANa,*, N. THIRUNAVUKKARASUb, M. B. GOVINDARAJULUb,

F. SASSEc, R. JANSENd, T. S. MURALIa,1
a
Vivekananda Institute of Tropical Mycology, RKM Vidyapith, RKM Vivekananda College, Chennai, India
b
PG & Research Department of Botany, RKM Vivekananda College, Chennai, India
c
Helmholtz Centre for Infection Research, Department of Chemical Biology, Braunschweig, Germany
d
Helmholtz Centre for Infection Research, RG Microbial Drugs, Braunschweig, Germany

article info abstract

Article history: Horizontally transmitted fungal endophytes are an ecological group of fungi, mostly
Received 29 July 2009 belonging to the Ascomycota, that reside in the aerial tissues and roots of plants without
Accepted 29 July 2009 inducing any visual symptoms of their presence. These fungi appear to have a capacity
to produce an array of secondary metabolites exhibiting a variety of biological activity.
Keywords: Although the ability of fungi to produce unique bioactive metabolites is well known, endo-
Bioprospecting phytes have not been exploited, perhaps because we are only beginning to understand
Drug discovery their distribution and biology. This review emphasizes the need to routinely include endo-
Endophytes phytic fungi in the screening of organisms for bioactive metabolites and novel drugs; it also
Fungal metabolites underscores the need to use information obtained concerning fungal secondary metabolite
Mycotechnology production from other groups of fungi for a targeted screening approach.
ª 2009 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

1. Introduction explored for metabolites for clinical applications. Existing

drugs of fungal origin include b-lactam antibiotics, griseo-
For several years, natural products have been used directly fulvin, cyclosporine A, taxol, ergot alkaloids, and lovastatin.
as drugs or have provided the basic chemical architecture More new natural products of varied chemical structures are
for deriving such drugs. There are at least 200,000 natural continually being reported from fungi (Grabley and Sattler,
metabolites with bioactive properties (Bérdy, 2005). For 2003; Mitchell et al., 2008; Stadler and Keller, 2008). The
instance, about 52 % of the new chemicals introduced into versatile synthetic capability of fungi reflects their heterotro-
the market worldwide between 1981 and 2002 were natural phic and absorptive mode of nutrition and the ability to
products or their derivatives (Chin et al., 2006). Besides exploit a variety of substrates and habitats (Hyde, 2005;
plants, microorganisms constitute a major source of natural Suryanarayanan and Hawksworth, 2005). We know only
products with desirable bioactive properties. More than about 7 % of the estimated 1.5 million species of fungi
20,000 bioactive metabolites of microbial origin were known (Hawksworth, 2004), and only very few of these have been
by the end of 2002 (Bérdy, 2005). Fungi are among the most cultivated and screened for drug production. It is therefore
important groups of eukaryotic organisms that are being logical to postulate that we have only discovered a small

* Corresponding author.
E-mail address: t_sury2002@yahoo.com (T.S. Suryanarayanan).
1
Division of Biotechnology, Manipal Life Sciences Centre, Manipal, Karnataka, India
1749-4613/$ – see front matter ª 2009 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.fbr.2009.07.001
10 T. S. Suryanarayanan et al.

percentage of economically important metabolites of fungal that the endophytes survive in living tissues of plants for
origin. a short or prolonged period without producing any visible
symptoms. Endophytes have a cryptic existence and their
main role in the ecosystem appears to be that of decomposers,
2. Products of pharmaceutical importance
as they are among the primary colonizers of dead plant tissues
from fungi
(Kumaresan and Suryanarayanan, 2002; Hyde and Soytong,
2008; Oses et al., 2008). There is some evidence to suggest
Bacteria and fungi are well known for producing many novel
that a few endophytes protect plants against diseases (Arnold
chemicals that are directly used as drugs or function as lead
et al., 2003), ward off insect pests (Akello et al., 2007), and
structures for synthetic modifications (e.g. Kock et al., 2001;
increase the fitness of plants by enhancing their tolerance to
Bode et al., 2002; Donadio et al., 2002; Chin et al., 2006; Gunati-
abiotic stress (Redman et al., 2002; Bae et al., 2008); endophyte
laka, 2006; Lam, 2006; Mitchell et al., 2008; Stadler and Keller,
infection can also impose a significant cost on the host plant
2008). Although mycophenolic acid, the first fungal secondary
(Arnold and Engelbrecht, 2007). For a more detailed account
metabolite was obtained from Penicillium glaucoma as early as
of different aspects of fungal endophyte biology, refer to
1896 (see Bérdy, 2005), it was the tremendous success of peni-
Arnold (2007), Saikkonen (2007), Sieber (2007), and Hyde and
cillin as an antibiotic in the early 1940s that shifted the focus
Soytong (2008).
of natural product-based drug sources from plants to microor-
There are a few studies on endophytes as sources of
ganisms. In the 5 y from 2000 to 2005, 23 novel drugs obtained
natural products of pharmaceutical and agricultural impor-
from plants and microorganisms for treating various human
tance (e.g Tan and Zou, 2001; Gunatilaka, 2006). We suggest
disorders such as cancer, neurological disorders, infectious
that horizontally transmitted cryptic fungal symbionts
and cardiovascular diseases, metabolic and immunological
(namely the endophytes of non-grass plants) should to be
diseases and genetic disorders were brought to the market
screened for biologically active compounds with the intensity
(Chin et al., 2006). In the 9 y from 1993, about 1500 metabolites
with which the soil fungi have been previously investigated
have been reported from fungi to have anti-tumor or antibi-
(Tan and Zou, 2001; Smith et al., 2008). Endophytic fungi
otic activity (Peláez, 2005). Some of the recently approved
appear to be metabolically more innovative than soil fungi
drugs of fungal origin are micafungin, an anti-fungal metabo-
(Schulz et al., 2002) or fungi associated with algae (Schulz
lite from Coleophoma empetri (Frattarelli et al., 2004), mycophe-
et al., 2008) with regard to bioactive compounds. That they
nolate, a product of Penicillium brevicompactum used for
produce unique bioactive metabolites is well known (Mitchell
preventing renal transplant rejection (Curran and Keating,
et al., 2008; Stadler and Keller, 2008). This is perhaps an
2005), rosuvastatin from Penicillium citrinum and P. brevicompac-
outcome of their constant need to interact with the host
tum used for treating dyslipidemias (Scott et al., 2004) and cef-
milieu. Endophyte–plant host interactions are different from
ditoren pivoxil, a broad spectrum antibiotic derived from
pathogen–plant host interactions since neither associate
Cephalosporium sp. (Darkes and Plosker, 2002). Derivatives of
really ‘wins’; neither disease symptoms develop on the plant
fumagillin, an antibiotic produced by Aspergillus fumigatus
host nor is the fungus eliminated by the plant host (Pinto
(Chun et al., 2005), and illudin-S, a sesquiterpenoid from
et al., 2000; Schulz et al., 2002; Stone et al., 2004; Sieber, 2007;
Omphalotus illudens (McMorris et al., 1996) exhibit anti-cancer
Saikkonen, 2007). This situation entails sustained and pro-
activities. Fungal metabolites find important applications in
longed reactions against the defense mechanisms of the
agriculture as well (Anke and Thines, 2007). It is pertinent to
host by the endophyte and this could act as selection pressure
mention that, among the microfungi, only certain genera
for developing novel metabolic pathways – a potentially bene-
such as Aspergillus and Penicillium have been rigorously
ficial situation for bio-prospectors (Calhoun et al., 1992; Schulz
screened for bioactive compounds; of the 6450 bioactive
et al., 1995; Lu et al., 2000; Wang et al., 2000; Tan and Zou, 2001;
metabolites from microfungi, more than 30 % are obtained
Weber et al., 2007).
from these two genera (Bérdy, 2005).
Although the advent of combinatorial chemistry has shifted
the research focus away from natural products, fungal endo-
3. Horizontally transferred fungal endophytes phytes continue to be a source for novel drugs (Strobel and
and bioprospecting Daisy, 2003; Wang et al., 2004; Bérdy, 2005; Mitchell et al., 2008;
Sappapan et al., 2008; Wang et al., 2008); they produce an array
Horizontally transmitted fungal endophytes are an ecological of metabolites of varied structural groups such as terpenoids,
group of fungi mostly belonging to the Ascomycota that reside steroids, xanthones, chinones, phenols, isocoumarins, benzo-
in the aerial tissues and roots of plants without inducing any pyranones, tetralones, cytochalasines and enniatines (Schulz
visual symptoms of their presence (Sánchez-Márquez et al., et al., 2002). The metabolites of endophytic fungi include anti-
2007; Oses et al., 2008; Rungjindamai et al., 2008; Tao et al., bacterial, anti-viral, anti-fungal and anti-cancer activities
2008). Although the existence of symptomless fungi inside (Gunatilaka, 2006). Some of the metabolites are xanthine
plant tissues has long been recognized [the term endophyte oxidase inhibitors toxic to brine shrimps, eosinophil inhibitors,
was coined by de Bary (1866)], it is only recently that horizon- acetylcholinesterase inhibitors, b-glucuronidase inhibitors,
tally spread fungal endophytes have been studied in detail by insecticides, root growth accelerators, anti-inflammatory
mycologists, ecologists and plant pathologists (Arnold, 2007; agents and insulin receptor activators (Gunatilaka, 2006).
Sieber, 2007; Saikkonen, 2007; Hyde and Soytong, 2008). The Fungal endophytes associated with higher plants appear to
term ‘endophyte’ has been variously defined (see Hyde and be a good source of novel anti-oxidants as well (Huang et al.,
Soytong, 2008), all of which are variations of the central theme 2007, 2008).
Fungal endophytes and bioprospecting 11

A few endophytes have been screened for novel antibiotics also bring about stereoselective biotransformations of chemi-
(Li et al., 1996; Zou et al., 2000; Bérdy, 2005; Shiono et al., 2005; cals, thus aiding in drug modifications (Borges et al., 2007).
Silva et al., 2005; Gu et al., 2007; Phongpaichit et al., 2007; Lös- Endophytes of tropical plants, constitute a species rich ecolog-
gen et al., 2008). There are reports of anti-cancer chemicals ical assemblage of fungi (Arnold and Lutzoni, 2007; Huang
from endophytes (Firáková et al., 2007) such as paclitaxel et al., 2008) and considering the synthetic potential of endo-
(Stierle et al., 1993), Hsp 90 inhibitors (Turbyville et al., 2006), phytes, they should be included in any program that aims at
sequoiatones A and B (Stierle et al., 1999) and camptothecin screening of fungi for novel metabolites.
(Amna et al., 2006). Novel compounds of endophyte origin Our experience with fungal endophytes isolated mostly
include new lactones (Chen et al., 2003), and enalin derivative from dicotyledonous trees of different types of forests of
(Hormazabal et al., 2005), colletotrichic acid (Zou et al., 2000), southern Western Ghats also suggests that endophytes are
myrocin A and apiosporic acid (Klemke et al., 2004), phomop- a promising source of bioactive compounds. We screened
silactone (Silva et al., 2005), cyclopentanoids (Teuscher et al., fungal endophytes isolated from 55 dicotyledonous trees
2006), and (þ)-ascochin and (þ)-ascodiketone (Krohn et al., belonging to 29 families and growing in dry deciduous, dry
2007), chaetocyclinones (Lösgen et al., 2007), pestalotheols thorn, moist deciduous or evergreen forests of the Nilgiri
A–D (Li et al., 2008), isofusidienols (Lösgen et al., 2008) and Biosphere Reserve, Western Ghats for bioactive metabolites.
naphthoquinone spiroketals (Macı́as-Rubalcava et al., 2008). The endophytes were grown as static cultures in Potato
The presence of endophytes in plant tissues can influence Dextrose broth for 20 d at 27  C. Secondary metabolites from
the volatiles produced by the plant (Mucciarelli et al., 2007). Jal- the culture filtrates were obtained by solvent extraction and
low et al. (2008) reported that Acremonium strictum, an unspe- tested for their effects on seed germination and plant cell divi-
cialized root endophyte, modifies the volatile profile of the sion, and for their anti-algal, anti-fungal and anti-insect prop-
host plant thereby influencing host selection and oviposition erties. Of the 107 isolates tested on rice seeds, 40 %–50 %
behaviour of a polyphagous moth. Jimenez-Romero et al. inhibited and promoted root growth, respectively; nearly
(2008) isolated lactones from endophytic Xylaria sp. with 98 % of the isolates reduced the plumule growth (Fig 1a, b).
potential to function as leads for anti-malarial drugs. Apart About 95 % of the 44 isolates screened reduced the mitotic
from elaborating novel bioactive chemicals, endophytes can index in onion root meristem while 7 % increased the mitotic

a 40

30
Length (mm)

20

10

0
Control 53 54 69 71 75 79 99 113 116 132
Endophyte Isolate

b 75
Length (mm)

50

25

0
Control 57 58 61 62 65 66 83 84 95 142
Endophyte Isolate

Fig. 1 – (a) Box-Whisker plots comparing the rank medians of the length of radicle of germinating rice grains (ADT 43) treated
with culture filtrates of select endophytes. Bars below and above the boxes indicate minimum and maximum values. The
bottom and top horizontal lines of a box represent the 25 and 75 percentile values with the median value indicated by a line
within a box. (b) Box-Whisker plots comparing the rank medians of the length of radicle of germinating rice grains (ADT 43)
treated with culture filtrates of select endophytes. Bars below and above the boxes indicate minimum and maximum values.
The bottom and top horizontal lines of a box represent the 25 and 75 percentile values with the median value indicated by
a line within a box.
12 T. S. Suryanarayanan et al.

index (Fig 2). Culture filtrate extracts of 56 % of the 145 endo- produced apicidin which is a histone deacetylase inhibitor
phyte isolates showed insecticidal activity. Similarly, 15 %– that inhibits cell division (Han et al., 2000), and enniatins
37 % of the 148 isolates showed anti-fungal and anti-algal which are known to function as inhibitors of the yeast trans-
activity, respectively. porter protein Pdr5p (Hiraga et al., 2005).
We screened 110 of these fungal endophyte isolates for Our study with 150 endophyte isolates using different
their anti-cancer activity by treating cells of mouse fibroblast bioassays showed that certain genera such as Alternaria, Chae-
cell line L-929 with organic solvent extracts of the culture tomium, Colletotrichum, Curvularia, Nigrospora and Xylaria
filtrates. Cytotoxic effects of the fractions of the culture produce a larger number of bioactive compounds.
filtrates were assessed by MTT colorimetric assay (Mosmann,
1983). Subsequently, the extracts showing activity were frac-
tionated by analytical RP HPLC and all the fractions (each 4. Plant–endophyte interactions affect
0.5 min) were tested for cytotoxic effects. Furthermore, the metabolite production
effects of the active fractions on nuclear morphology, cell divi-
sion, actin microfilaments and endomembrane system of PtK2 Our knowledge of interaction of horizontally transmitted
potoroo cells were studied using immunofluorescence tech- fungal endophytes with their plant host at any level, be it
niques. These bioassays revealed that some of the endophytes structural, physiological or gene level, is, at best, unclear.
produced metabolites that impair cell division. Active extracts The endophytes are likely to adopt the same strategy as the
were further analyzed by HPLC-MS. Biological and analytical plant pathogenic fungi in order to enter a plant host (Chapela
information together with information from databases (DNP et al., 1993; also see Sieber, 2007 and Stone and Petrini, 1997).
on CD-ROM) helped to identify known compounds. Notable Even such a generalization has to be made with some caution:
among the active endophytes was a Chaetomium sp. that in the case of direct-penetrating biotrophic fungal pathogens,
produced chaetoglobosins, which are cytochalasin analogs the epidermal surface of the host is the first line of defense
that inhibit actin polymerization (Yahara et al., 1982) (Fig 3). explaining to a certain extent host-specificity among them
Chaetomium is a genus known to produce different types of (Viret et al., 1994; Heath, 2002; Valkama et al., 2005). Even
secondary metabolites including chaetomin, chaetoglobosins, though both endophytes and biotrophs derive nutrients
chaetoquadrins, oxaspirodion, chaetospiron, orsellides and from their hosts without killing them, many endophytes
chaetocyclinones (Lösgen et al., 2007). A Phomopsis sp. such as Phomopsis, Phoma, Colletotrichum and Phyllosticta have
produced phomopsolide A and B which have been reported a wide host range and colonize several taxonomically unre-
to act as boring and feeding deterrents of elm bark beetles lated plant hosts (Pandey et al., 2003; Jeewon et al., 2004; Murali
(Grove, 1985). An Alternaria endophyte elaborated several sol- et al., 2006; Sieber, 2007) suggesting that they have developed
anapyrones (Table 1 and Fig 4). These phytotoxic compounds adaptations to overcome different types of host defences.
are inhibitors of DNA polymerases (Mizushina et al., 2002). Apart from the balanced antagonism hypothesis proposed
Endophytic Nigrospora oryzae produced aphidicolin (3a, 16b, by Schulz et al. (1999) attempting to explain the type of inter-
17, 18-Aphidicolianetetrol – Fig 4) and several of its deriva- action between fungal endophytes and their plant hosts, there
tives, nigrosporolide, phomalactone, bostrycin and epoxyex- is little information on the post-penetrative stages of endo-
serohilone. Aphidicolin is a tetracyclic diterpene-tetraol and phyte–host interaction. Abang et al. (2009) showed that the
an inhibitor of nuclear DNA synthesis in eukaryotes (Spadari asymptomatic endophytic Colletotrichum gloeosporioides is
et al., 1982). It inhibits DNA synthesis by interfering with unable to produce a toxic metabolite which the pathogenic
DNA polymerase a enzyme. Ikegami et al. (1979) reported strains produced and induced disease symptoms in the plant
that this metabolite inhibits the S phase of the cell cycle. host. It is not clear if several post penetration defense reac-
Nigrosporolide is a 14 membered lactone which inhibits plant tions of the hosts such as programmed cell death, induction
growth and was first reported from Nigrospora sphaerica (Har- of phytoalexins and pathogenesis related proteins observed
wooda et al., 1995). Furthermore, one of our Fusarium isolates for pathogen–host interactions (De Lorenzo and Ferrari,

3
Mitotic index

0
Control 53 66 73 76 77 79 87 88 91 93 59 60 100
Endophyte Isolates

Fig. 2 – Effect of endophyte secondary metabolites on cell division in onion root meristem (bars represent standard
deviation).
Fungal endophytes and bioprospecting 13

Fig. 3 – Effect of culture extract from endophytic Chaetomium sp. on potoroo kidney cell line PtK2. Note cell enlargement, loss
of actin fibres and failure of cell division after nuclear division. (Nucleus stained with blue fluorescent dye and actin with red
fluorescent dye).

2002) are also operative in endophyte–host interactions endophytes producing novel biochemicals. Endophytic fungi
(Sieber, 2007). The observation of Moricca and Ragazzi (2008) associated with traditionally used medicinal plants especially
indicates that the type of interaction between an endophyte of the tropics could be a rich source of functional metabolites
and a plant is controlled by the genes of both organisms and (Weber et al., 2004; Tejesvi et al., 2007; Aly et al., 2008; Boonman
modulated by the environment. A benign endophyte residing et al., 2008; Huang et al., 2008; Sappapan et al., 2008). In this
in the host tissue in a symptomless state or one that may be regard, the endophyte–plant host association could also be
beneficial to its host may turn into a pathogen in response exploited in enhancing the production of useful metabolites
to some environmental cue (Hendry et al., 2002). It is logical by the plant host (Wang et al., 2004). In addition to plants of
to assume that such a shift in the nature of the endophyte the tropical rain forests, those growing in harsh habitats such
would also result in a change in its metabolite profile. Patho- as hot and cold deserts, saline and acidic soils and marine habi-
genic fungi can reside as symptomless endophytes in plant tats have to be screened for bioactive metabolite-producing
tissues (Kuldau and Yates, 2000; Vettraino et al., 2005; Surya- endophytes (Raghukumar, 2008; Schulz et al., 2008).
narayanan and Murali, 2006); futhermore, the species diver- We observed some tissue-specificity but less host taxon
sity of foliar endophyte assemblage is known to change with specificity in endophytes associated with mangrove trees
the leaf age (Stone, 1987; Okane et al., 1998; Taylor et al., (Kumaresan et al., 2002). Pang et al. (2008) obtained similar
1999; Photita et al., 2004; Suryanarayanan and Thennarasan, results for endophytes of Kandelia candel growing in Hong
2004). These facts indicate that sampling endophytes from
a plant community for bioprospecting on a single occasion
may not capture the entire spectrum of endophytes and their
Table 1 – Some bioactive secondary metabolites isolated
metabolites. The effort has to be sustained to obtain the whole
from endophytic fungi in our study
extent of secondary metabolites.
Fungus Chemical list
The endophyte may be in a metabolically aggressive envi-
ronment constantly encountering host defense chemicals Phomopsis sp. Phomopsolide A
(Cabral et al., 1993; Peters et al., 1998; Schulz et al., 1999). Such Phomopsolide B
a hostile environment may account for the evolution of the Chaetomium sp. Chaetoglobosin A
Chaetoglobosin C
potentially increased synthetic ability of the endophytes.
Chaetoglobosin D
This perhaps explains the apparent anomaly observed when
Chaetoglobosin G
a species of endophyte isolated from a plant host produces Alternaria alternata Prosalanapyrone I
a bioactive compound but fails to do so when isolated from Prosalanapyrone II
another plant species (Li et al., 1996). We have found that the Prosalanapyrone III
herbicidal activity of secondary metabolite(s) of an endophytic Solanopyrone A, B, C, D, E, F, G
Phyllosticta capitalensis differed with the plant host from which Nigrospora oryzae Aphidicolin
Aphidicolene
the endophyte was isolated. This probably means that the
Aphidicolaneodiol
plant host (and ultimately its metabolism) influences the
Aphidicolanatriol
synthetic ability of an endophyte. This indicates that biopro- Aphidicolanepentol
specting for endophyte natural products should be host plant Curvularia sp. Cytochalasin B
based as opposed to fungal taxon based. Strobel and Daisy Cytochalasin F
(2003) emphasize this in their review while stating that ‘plants Fusarium sp. Apicidin
from unique environmental settings’ and ‘plants with an Enniatin A1
Enniatin B
unconventional biology’ as well as plants with established
Enniatin E
ethnobotanic values would be more promising sources of
14 T. S. Suryanarayanan et al.

Fig. 4 – Structure of the some bioactive secondary metabolites isolated from endophytic fungi in our study.
Fungal endophytes and bioprospecting 15

Kong mangroves. Endophytes should therefore be screened potential of fungal secondary metabolites could also be fully
from different tissues of a host plant rather than targeting realized by the application of combinatorial techniques
endophytes isolated from similar tissue of different plant (Pirrung et al., 2006).
species (Hyde and Soytong, 2008). In fungi, genes coding for enzymes of secondary metabolic
The endophyte–host relationship possibly involves the pathways usually occur as gene clusters being situated in the
evolution of strategies and counter strategies by the mutual- same locus and co-expressed (Keller and Hohn, 1997; Bok
ists. Different species of the horizontally transmitted endo- et al., 2006). These gene clusters are known to evolve rapidly
phytic fungi cause multiple and discrete infections in through multiple rearrangements, duplication and losses,
a given tissue of a plant such as a leaf (Fisher and Petrini, and are capable of interspecific spread through horizontal
1987; Suryanarayanan et al., 1998, 2000, 2002; Arnold et al., gene transfer (Khaldi et al., 2008). Such properties are condu-
2000; Fröhlich et al., 2000; Gamboa and Bayman, 2001). It is cive for synthesis of novel chemicals by organisms and provide
not known if such an interaction of different species of endo- reason to strengthen the need for targeting fungal endophytes
phytes (or an interaction between endophytes and pathogens) for bioprospecting. It is important to screen fungal species for
in a given host tissue attenuates or enhances the metabolic their secondary metabolite spectrum under different growth
capability of one another. The work of Bailey et al. (2006) indi- conditions; culture parameters such as composition of growth
cates that endophyte infections alter the pattern of gene medium, aeration, pH and the presence of certain enzyme
expression in the host plant. Assays of endophytes in single inhibitors change dramatically the secondary metabolite
and multiple infections under in vitro conditions (using callus profile and even induce the synthesis of several new metabo-
or cell cultures) would provide some insights into this, ulti- lites (Bode et al., 2002). For example in Aspergillus flavus, the
mately leading to devising procedures to obtain better yields genes involved in secondary metabolism show higher levels
of the metabolites of interest (Pirttilä et al., 2004). of expression at 28  C than at 37  C (OBrian et al., 2007).
Only endophytes associated with angiosperms and As far as drug discovery is concerned, screening of libraries
gymnosperms have been studied to any extent for novel created by combinatorial synthesis once appeared to be more
metabolites. Endophytes of other taxonomic groups of plants promising than natural products screening (Fehér and
such as algae, bryophytes, pteridophytes and even lichens Schmidt, 2003; Ortholand and Ganesan, 2004). Though combi-
(Suryanarayanan et al., 2005; Zhang et al., 2006; Li et al., 2007) natorial synthesis can churn out molecules in enormous
should be included in screening programmes. For example, numbers, endophytic fungi can still be a good source of novel
the non-obligate, asymptomatic fungi occurring within lichen drugs and natural product-based scaffolds for combinatorial
thalli appear to be an untapped source of secondary metabo- synthesis and libraries (Wang et al., 2006a,b; Ge et al., 2008).
lites (Li et al., 2007; Paranagama et al., 2007). Similarly, the This is because the synthetic capability of endophytes, like
endophytic fungi associated with marine algae also appear in other organisms, has been fine tuned by natural selection
to synthesize novel metabolites (Wang et al., 2006a,b; Lösgen over millions of years (Fehér and Schmidt, 2003; Taylor,
et al., 2007; Zhang et al., 2007). 2008). Smith et al. (2008) combined sequence analysis with
bioassay procedures to explore the endophyte diversity of
the tropics. Their results suggest that tropical plants harbour
5. Discovering novel chemicals in a sizeable portion of undiscovered endophytes which may
undiscovered endophytes be vested with novel biochemical diversity. Hence the need
for the inclusion of fungal endophytes in natural products
Not all endophytes are culturable (Higgins et al., 2006) and discovery programmes. Testing endophytes isolated from
these may produce useful metabolites. There are several different tissues of plant hosts (rather than those isolated
methods to detect unculturable fungi and these include whole from the same organ of different plant hosts) and from plants
DNA analysis followed by DNA cloning (Guo et al., 2001; Seena growing in unusual and less-studied habitats will be more
et al., 2008), DGGE (Duong et al., 2006; Tao et al., 2008) or T-RLFP productive. We suggest a global initiative involving fungal
(Nikolcheva and Bärlocher, 2004, 2005). Therefore, apart from taxonomists, ecologists, and natural product chemists to
isolating culturable endophytes from different taxonomic evolve systematic and rapid screens for endophytic fungi by
groups of plants and plants growing in different habitats, designing strategic bioassays that would indicate the produc-
shotgun metagenomics for endophyte community analysis tion of novel bioactive compounds.
and function-based screening of their metagenomic libraries
could be used to harness the unculturable and truly cryptic
endophytes from environmental samples for drug production. Acknowledgements
Such a metagenomic approach has been quite rewarding with
soil samples (Kimura, 2006). Metabolomics of endophyte- TSS thanks Swami Atmaghanananda, Chairman, VINSTROM,
infected and endophyte-free plant hosts could reveal junc- for facilities, the Department Biotechnology, Government of
tions in secondary metabolite pathways which may be India for funding the Indo-German Research Project (BT/IN/
nudged into synthesizing novel chemical species or lead FRG/TSS/2003-4) and Prof. R. Sukumar, CES, IISc, Bangalore
compounds – another possibility of exploiting these chemodi- for helping in the collection of samples from the forests. FS
verse organisms (Jewett et al., 2006). Furthermore, other novel gratefully acknowledges the skillful technical assistance of
techniques such as radiochemical labeling can be used for Bettina Hinkelmann. TSS dedicates this work to his mentor
detecting products of genes with low expressions among Dr. R. N. Swamy, Retired Professor, Centre for Advanced Study
endophytes (Miljkovic et al., 2008). In addition, the biological in Botany, University of Madras.
16 T. S. Suryanarayanan et al.

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