Applied Microbiology and Biotechnology

https://doi.org/10.1007/s00253-018-9101-7

MINI-REVIEW

Production of bioproducts by endophytic fungi: chemical ecology,

biotechnological applications, bottlenecks, and solutions
Lu Yan 1 & Haobin Zhao 1 & Xixi Zhao 1 & Xiaoguang Xu 1 & Yichao Di 1 & Chunmei Jiang 1 & Junling Shi 1 & Dongyan Shao 1 &
Qingsheng Huang 1 & Hui Yang 1 & Mingliang Jin 1

Received: 3 April 2018 / Revised: 12 May 2018 / Accepted: 14 May 2018

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Endophytes are microorganisms that colonize the interior of host plants without causing apparent disease. They have been widely
studied for their ability to modulate relationships between plants and biotic/abiotic stresses, often producing valuable secondary
metabolites that can affect host physiology. Owing to the advantages of microbial fermentation over plant/cell cultivation and
chemical synthesis, endophytic fungi have received significant attention as a mean for secondary metabolite production. This
article summarizes currently reported results on plant-endophyte interaction hypotheses and highlights the biotechnological
applications of endophytic fungi and their metabolites in agriculture, environment, biomedicine, energy, and biocatalysts.
Current bottlenecks in industrial development and commercial applications as well as possible solutions are also discussed.

Keywords Endophyte . Mutualism . Interaction benefit . Adversity tolerance . Nutrient acquisition . Biocontrol . Bioproduct

Introduction and/or consequences of these interactions are evident in the

In view of population growth and the need for sustainable
economies, it has become urgent to dramatically improve the
productivity of agricultural crops and other food sources. In
addition, market demands for energy, medicine, and other as-
pects related to bioproducts are growing at an accelerated rate
(Venugopalan and Srivastava 2015). Fungi are known to be a
treasury of medical compounds since the discovery of peni-
cillin. Subsequent reports of taxol-producing endophytes in-
spired the hope that fungal endophyte-based biotechnology
could be a promising alternative way to produce valuable
biological products (Kusari et al. 2014).
The term Bendophyte^ originally referred to organisms
(e.g., fungi, bacteria, algae, insects, and other vascular plants)
that colonize the interior of host plants without causing overt
symptoms (Behie and Bidochka 2014a; Carroll 1988). The
majority of currently available publications on endophytes
have focused on fungi, and in some instances, Bsymptoms^
* Junling Shi
sjlshi2004@nwpu.edu.cn
1
Key Laboratory for Space Bioscience and Biotechnology, School of
Life Sciences, Northwestern Polytechnical University, 127 Youyi
West Road, Xi’an 710072, Shaanxi Province, China
host plant (Arnold et al. 2005). Almost all plants in natural
ecosystems appear to be in some kind of symbiotic relation-
ship (which can range from mutualistic to pathogenic) with
fungi (Aly et al. 2011; Rodriguez et al. 2009). Based on dif-
ferences in evolutionary relatedness, taxonomy, host plants,
and ecological functions, endophytic fungi have been classi-
fied into two major groups: clavicipitaceous endophytes (C-
endophytes) and non-clavicipitaceous endophytes (NC-
endophytes) (Rodriguez et al. 2009). In combination with
our increasing understanding of their diversity, ecological
roles, and potential for various biotechnological applications,
interest in NC-endophytes has steadily increased in recent
years.
A significant literature exists indicating that endophytes
frequently confer increased plant resistance to biotic and abi-
otic stresses (Selosse and Tacon 1998). Compared with con-
trol groups, plants with fungal endophytes are capable of bet-
ter resisting phytopathogens, acquiring nutrients, and show
enhanced plant growth (Field et al. 2015). One of the possible
reasons for this beneficial relationship is that some endophytes
have the ability to produce a range of bioactive metabolites
(Pan et al. 2017). Such capabilities provide these endophytic
fungi with the potential for the biosynthesis of compounds
useful in agriculture, medicine, and other human health-
related fields (Mousa et al. 2015). In this regards, the

commercial exploitation of endophytes as a promising source
of valuable products in biotechnological applications are in
progress (Suryanarayanan et al. 2012).
However, a significant obstacle has been the incremental
success in the industrial-scale production of bioactive com-
pounds from fungal endophytes. A growing number of reports
suggest variation and unstable production of such valuable
products during cyclic culturing of endophytes independent
of their host plants (Kusari et al. 2011). This has led to doubts
in scientific community about the feasibility of biotechnolog-
ical prospects of endophytes. Hence, it is of vital importance
to understand the chemical ecology of endophytes, the inter-
actions with their host plants, and the conditions required for
syntheses of these secondary metabolites (Kusari et al. 2014).
Significant efforts have been expended to reveal these com-
plicated interactions; meanwhile, a timely summary of these
proposed hypotheses is imperative for in-depth study
(Redecker et al. 2000; Schulz et al. 1999). In order to obtain
a deeper insight into the potential application of endophytes,
an overview of the interactions between endophytes and their
hosts is summarized in this review. Subsequently, current ap-
plications of endophytic fungi in various biotechnological
fields will be highlighted, and current bottlenecks and future
prospectives will be discussed.
Plant-endophyte interaction—chemical
ecology of secondary metabolite production
by endophytes
Findings of fossilized fungal hyphae and spores over 460
million years old suggest that fungi have been important
partners for the successful colonization of land by plants
(Redecker et al. 2000). Current models firmly support that
endophytes are beneficial for plant fitness (Rodriguez et al.
2008; Yu et al. 2017). However, for any plant-fungal inter-
action to occur, it must be preceded by a physical encounter
and a number of biological and chemical barriers must be
overcome in order for a successful association to be
established (Kusari et al. 2012a). Two of the most interest-
ing questions in this field is how can endophytes remain
within plants asymptomatically? And how can the fungi
benefit their plant hosts? A number of current possible hy-
potheses are summarized as below.
Balance between plant defense and microbial
virulence
One of the mechanisms for endophytes asymptomatically col-
onizing within plants is that the secondary metabolites pro-
duced by endophytic fungi can antagonize the toxic metabo-
lites of the host defenses to ensure survival. The balanced
Appl Microbiol Biotechnol
antagonism hypothesis posits that a balance exists between
plant defensive responses to endophytes and the toxic effect
of endophytes on plants (Schulz et al. 1999). The plant im-
mune system tends to defend plants from all microbial in-
vaders: when endophytes invade the host plant, the defense
response is activated and limits the development of the endo-
phyte and of the corresponding disease. To achieve asymp-
tomatic survival, endophytes produce metabolites that over-
come host defense responses to the fungus, resulting in com-
patible multipartite symbiosis (Schulz et al. 2015, 1999). In
addition, the fungus may maintain a balanced antagonism
with other microbial competitors. If fungal virulence and plant
defense are balanced, the association between fungi and their
host plants may remain apparently asymptomatic. In contrast,
if plant defenses are defeated by fungal activities, the associ-
ation will lead to a plant-pathogen interaction and thus lead to
plant disease (Fig. 1). Evidence is that taxol is produced by
endophytic fungi (Paraconiothyrium SSM001) of plant yews
to resist pathogens. However, overly abundant taxol is harm-
ful to the plant itself by disrupting plant cell cytokinesis
(Soliman et al. 2015).
Co-evolutionary adaptation of endophytes
and the plant hosts
During the long-term interaction, endophytes have evolved
sophisticated mechanisms to modulate plant innate immune
responses instead of just balance between virulence and plant
defense (Erik et al. 2015; Nürnberger et al. 2004; Zamioudis
and Pieterse 2012). For example, β-glucan is an important
part of the fungal cell wall and is also one of the essential
compounds that can trigger the plant immune system. The
FGB1 gene from the root endophyte Piriformospora indica
encodes a secreted fungal-specific β-glucan-binding lectin
that has the potential to alter fungal cell wall composition
and properties. In this way, endophytes tend to efficiently
suppress β-glucan-triggered immunity in different plant hosts
(Wawra et al. 2016). During their co-evolutionary adaptation
and the ensuing Barms race^ between hosts and pathogenic
microorganisms, plants that evolve defenses including the
production of secondary metabolites are better able to defend
against pathogen. Microbial pathogens that then evolve re-
sistance mechanisms including structural changes of effect
targets are able to overcome plant defenses. Plants can gain
an advantage in this arms race by developed inhibitors that
target pathogenic microbes, thus gaining a significant evo-
lutionary advantage. One mechanism by which such anti-
microbial compounds can be recruited by plants is via as-
sociation with endophytic microbes that secrete secondary
metabolites that assist in plant defense (Li and Zhang
2008; Stermitz et al. 2000).
Appl Microbiol Biotechnol
Fig. 1 Schematic representation of the balanced antagonism hypothesis
in plant. a When endophytes invade the host plant, the defense response is
activated and the produced molecules limits the development of
endophyte. Endophytes produce metabolites to overcome the host
defense response. b If fungal virulence and plant defense are balanced,
Assisting hosts as acquired immune systems
According to the mosaic effect hypothesis, endophytes may
produce heterogeneous chemicals within and among plant or-
gans that tend to vary the appeal for herbivores and infectivity
for pathogens (Carroll 1991). In addition, the presence of en-
dophytes in plants may assist their hosts as Bacquired immune
systems^ (Arnold et al. 2003). Endophytes expand plant im-
munity by acting as autonomous, antipathogen sentinels,
monitoring the vascular system. For examples, in yews
(Taxus) that associate with taxol (that can act as an antimicro-
bial compound)-producing fungal endophytes, persistent bark
cracking and deep air pockets potentially allow pathogens to
enter the nutrient-rich vascular system. The endophytes accu-
mulate taxol in hydrophobic bodies, that migrate to potential
pathogen entry points in the plant, and release the bodies upon
sensing microbial pathogens to create fungicide-laced barriers
for their hosts (Soliman et al. 2015).
Genetic potential origins of secondary
metabolites
Great effects have been made on the isolation of endophytic
fungi able to produce valuable plant-derived drugs. However,
numerous studies have shown the often variable and unstable
yields in the production of desired secondary metabolites from
various endophytic fungi isolates, including under axenic con-
ditions, which can have a huge impact on efforts aimed at
large-scale cultivation and isolation of valuable metabolites.
As for the genetic origins of secondary metabolites appeared
in both plants and endophytes, three schools of thought exist.
the association between fungi and their host plants will maintain a
balanced antagonism. c If the plant defense is defeated by fungal
virulence, the association will be the plant-pathogen relationship and thus
lead to plant disease.
According to Kusari et al. (2011), the camptothecin-
producing endophytic fungus (Fusarium solani) required the
host strictosidine synthase (STR) to complete the biosynthesis
of camptothecin. In addition, the sequence alignments of
biosyhthetic enzymes have shown high homology (> 96% se-
quence identity) between the fungal and plant genes
(Fitzpatrick 2012; Sah et al. 2017; Zhang et al. 2009; Zhou
et al. 2007). Thus, this thought claims that the gene clusters of
these metabolites may have been horizontally transferred be-
tween host plants and microbes during their co-evolution.
Both the host plants and endophytic fungi have evolved in-
trinsic resistance mechanisms to protect themselves against
endogenic toxic metabolites such as taxol and camptothecin.
On the contrary, another thought argues that both plants
and endophytes have parallel pathways to produce valuable
secondary metabolites. Xiong et al. (2013) reported that the
key genes of the taxol biosynthetic cluster have lower similar-
ities (~ 42%) between microorganisms and plants, suggesting
divergence and/or independent origins. Furthermore, the ge-
nome sequence of the endophytic fungus Penicillium
aurantiogriseum has revealed that the paclitaxel biosynthetic
genes are significantly different from those found in the plant
Taxus genus, indicating that horizontal gene transfer is unlike-
ly to have occurred. Thus, endophytic fungi may have evolved
to independently synthesize some of these secondary metab-
olites found in both plants and fungi (Yang et al. 2014).
The third thought claims that the capability of endophytic
fungi to mimic, i.e., produce, compounds similar to plant host
secondary metabolites has led to the question of whether these
compounds actually produced by endophytic fungus (Kusari
et al. 2012a). Evidence is that sustainable production of me-
tabolites such as taxol by the axenic culture of endophytic
fungi has been reported (Zhao et al. 2013a).

Currently, a lack of comprehensive understanding of chem-
ical ecology and intrinsic mechanism of these interactions has
been the major bottleneck in the commercialization. Further
study at the gene level is still required to reveal the truth of
both similarity and difference between endophytes and plants.
Biotechnological application of endophytic
fungi
Based on the relationship between endophytic fungi and their
host plants, endophytic fungi have been applied in agriculture,
environment, biomedicine, energy, and biocatalysts.
Theoretically, such benefits of plant-endophyte relationships
can be summarized below and as shown in Fig. 2.
Application in agriculture industry
During the plant-endophyte association co-evolution, plants
have acquired numerous benefits from fungal endophyte col-
onization (Bartels and Sunkar 2005; Bohnert et al. 1995). In
particular, the interactions of fungal endophytes with their
plant hosts can modulate plant responses and various biotic
and abiotic stresses, expanding the genetic toolkit available to
plants that can enable them to increase resistance to these
stresses.
Adversity tolerance
Perhaps one of the most striking benefits that plants gain from
associating with endophytic fungi is an increase in the ability
Fig. 2 Application of endophytic
fungi in the biosynthesis of
functional biomaterials
Appl Microbiol Biotechnol
to resist various forms of abiotic stress. As an example, it
has been shown that P. indica, a root-colonizing endophytic
fungus of Sebacinales, can induce drought tolerance in
Brassica campestris (Chinese cabbage plants) and salt tol-
erance in Hordeum vulgare (barley) (Baltruschat et al.
2008; Sun et al. 2010). According to Redman et al.
(2011), artificially colonized commercial rice varieties with
fungal endophytes isolated from plants growing across
moisture and salinity gradients exhibited enhanced salt
and drought tolerance. Endophytes were reported fastidious
in culture and limited to some cool- and warm-season
grasses (Rodriguez et al. 2009). These endophytes frequently
increase plant biomass as opposed to non-endophyte bearing
plants, confer greater drought tolerance, and produced
chemicals that are toxic to animals and decrease herbivory
(Hui et al. 2017). However, the benefits conferred by these
fungi appear to depend on host species, host genotype, and
environmental conditions (Cheplick 2004; Rodriguez et al.
2008). Broadly speaking, abiotic stresses, e.g., high salinity,
low moisture, heat, negatively affect plant physiology and
morphology, often leading to the production of damaging re-
active oxygen species (ROS), plant membrane dysfunction,
and hormonal imbalances that can negatively affect plant
health and growth (Egamberdieva et al. 2017). One possible
mechanism underlying increased plant stress tolerance has
been proposed to be due to increased levels of antioxidant
pathways, thereby preventing ROS-induced oxidative damage
in plants (Egamberdieva et al. 2017; Hardoim et al. 2015).
Increased antioxidant functioning can be due to production
of antioxidant enzymes/compounds by the endophytic fungi
themselves and/or by fungal effectors that stimulate plant an-
tioxidant pathways.
Appl Microbiol Biotechnol
Biocontrol of phytopathogens
Phytopathogenic fungi are a major threat to plant health and
production yield, causing diseases of many plant species all
over the world. Within agricultural practices, extensive use of
chemical pesticides to control plant pathogenic fungi has al-
ready resulted in the development of pesticide-resistant strains
(Liu et al. 2016). Endophytic fungi have been widely reported
to aid their host plants by increasing resistance to microbial
pathogenic invaders (Yu et al. 2017). Many examples have
illustrated the efficiency of endophytes for the biocontrol of
phytopathogens in vivo and in vitro (Singh et al. 2016). For
example, the endophytic fungi, Alternaria alternata, isolated
from grapevine leaves completely inhibited the sporulation of
the pathogen, Plasmopara viticola. The presence of either
enlarged vacuoles or vacuoles that contained electron-dense
precipitates was observed in P. viticola, which was attributed
to the secretion of three antifungal metabolites produced by A.
alternata (Musetti et al. 2006). The endophytes
Cryptosporiopsis sp. and Phialocephala sphareoides have al-
so been shown to significantly decrease the growth of mem-
bers of the well-known phytopathogens, Heterobasidion
parviporum, Phytophtora pini, and Botrytis cinerea, in vitro.
Metabolites secreted from Cryptosporiopsis sp. induced ab-
normal growth, cell distortions, thickening, and apical swell-
ing in the hyphae of competing fungal plant pathogens
(Terhonen et al. 2016). In addition, biocontrol of the nematode
plant pathogen, Meloidogyne incognita, by the endophytic
fungus, Acremonium implicatum, has shown that hyphae of
the fungus can penetrate the nematode shell and grow inside
the eggs, thus killing the pathogen (Yao et al. 2015). It can be
summarized that the utilization of endophytic fungi to sup-
press pathogens is via at least three mechanisms: production
of antibiotics, morphological changes, and egg parasitic and
hatching inhibition (Fig. 3). Other mechanisms, such as com-
petition for space and induction of overexpression of endoge-
nous antifungal or antibacterial compounds by plants, have
also been proposed (Ownley et al. 2008; Siddaiah et al. 2017).
Increase of nutrient acquisition and plant growth
Fungal endophytes can also influence plant growth via trans-
fer of nutrients to their plant hosts and/or by direct production
of or stimulating production of plant hormones (Kei et al.
2016; Khan et al. 2012). Plants with endophytic fungi exhibit
superior growth over those without endophytic fungi due to
fungal activities that include solubilizing different sources of
phosphorus, producing indole acetic acid, and transferring
scarce soil nutrients (e.g., nitrogen, phosphorus, and sulfur)
to plant hosts (Kiers et al. 2011; Priyadharsini and
Muthukumar 2017). For example, the dark septate endophytic
fungi possess the ability to degrade cellulose, starch, lipids,
casamino acids, urea, pectin, and gelatin, which is beneficial
for plants (Surono and Narisawa 2017). Furthermore, it is well
known that the combination of nitrogen-fixing root endo-
phytes within root nodules of leguminous leads to increased
plant growth and health (Hardoim et al. 2015). For example,
the endophytic fungus, Phomopsis liquidambari, can increase
the nodulation and N2 fixation of peanuts via enhancing
H2O2/NO-dependent signaling crosstalk (Xie et al. 2017).
Increasing evidence indicates that many fungal
entomopathogens that were almost exclusively considered
and studied as insect pathogens might play additional roles
as endophytes in nature (Jaber and Enkerli 2017). Vascular
plants lose a significant share of their nitrogen through insect
herbivory. Intriguingly, it has been found that nitrogen can be
cycled into plants through endophytic insect-pathogenic fungi
(Behie and Bidochka 2014a). The insect-pathogenic fungus
Metarhizium robertsii appears to couple root association
and/or endophytic capability and insect pathogenicity so that
it acts as a conduit to provide insect-derived nitrogen to plant
hosts, gaining carbohydrates in return (Behie and Bidochka
2014b), thus increasing the overall plant productivity (Behie
et al. 2012). Beauveria bassiana has been reported to naturally
and artificially colonize a number of different plants (Parsa et
al. 2013), promoting their growth (Jaber and Enkerli 2017).
These findings provide evidence that active nitrogen acquisi-
tion by plants in plant-endophyte-herbivore interactions may
play an important role in ecological nitrogen cycling.
Application in environmental remediation
Bioremediation of metalliferous soil and water
Continued worldwide industrialization accelerated the emis-
sion of various pollutants including heavy metals (Ma et al.
2011). These heavy metals seep from industrial runoffs and
water sources into soils and have caused serious environmen-
tal pollution and human health concerns (Deng and Cao
2017). Apart from the widely used physicochemical strategies
such as filtration, chemical precipitation, and electrochemical
treatment, in recent years, bioremediation has emerged as a
potential method to clean metal-contaminated soils (Xiao et al.
2010; Zahoor et al. 2017). Phytoremediation employing living
plants (especially hyperaccumulators) to degrade and detoxify
heavy metals from polluted soils have significant advantages
in terms of high efficiency and are eco-friendly. However,
high concentrations of heavy metal pollution can damage
plant metabolism and thus restrict their ability to functionally
remove the metals. Furthermore, slow plant growth and the
time needed during biomass accumulation pose severe limita-
tions to phytoremediation. However, recent research indicates
that endophytic fungi have an increased potential to assist in
plant tolerance to heavy metals (Deng et al. 2014; Khan et al.
2017). The fungi can remove metals via biotransformation
 Appl Microbiol Biotechnol

Fig. 3 Mechanism underlying

endophytic fungi suppression of
pathogens in host plants. (1) P.
viticola mycelium (P). (2) During
biological control of P. viticola by
A. alternate (Aa), vacuoles (V)
were enlarged that contained
electron-dense precipitates; the
plasmalemma was detached from
the wall; haustoria (Ha) were
necrotic, with an irregular shape
or surrounded by callose; three
antifungal metabolites produced
by A. alternata. (3) Hyphae of H.
parviporum (H). (4) During
biological control of H.
parviporum by Cryptosporiopsis
sp., hyphae swell, thickened, and
showed abnormal growth. (5)
Eggs of Meloidogyne incognita
(M) uninfected with complete
shells. (6) Eggs were penetrated
by A. implicatum hyphae (Ai),
and consequently, the shell
integrity was destroyed.

and/or accumulation of heavy metals present in the soil sur-
rounding plants in its hyphae, thereby reducing their availabil-
ity and toxicity to host plants (Khan et al. 2017). In this
regards, indole-3-acetic acid (IAA) produced by endophytic
fungal strains have been shown to promote plant biomass
accumulation and thus improve plant ability to remove the
metals.
In addition to accelerating phytoremediation of heavy
metal-contaminated soils, both active and dead endophytic
fungi possess the potential to remove heavy metals from water
and soils independent of a plant host. An endophytic fungus,
Lasiodiplodia sp. MXSF31, was isolated from the stem of
Portulaca oleracea growing in metal-contaminated soils.
The active biomass of the fungus accumulated more toxic
Cd, Pb, and Zn than the dead biomass from contaminated soils
and water (Deng et al. 2014). Studies have shown that one
mechanism of heavy metal biosorption could be attributed to
functional groups on the fungal surface that include hydroxyl,
amino, carbonyl, sulfonate, and benzene moieties presented
on the cell wall (Yang et al. 2012; Zahoor et al. 2017). It is
possible that the density of these functional groups is a factor
affecting adsorption efficiency. In order to enhance the
biosorption efficiency for metal ions, endophytic fungi could
be fashioned into a biosorbent by chemical modifications. For
example, the mycelium of mangrove endophytic fungus
Fusarium sp. was dried and powered as raw biomass and then
chemically modified by formaldehyde, methanol, and acetic
acid to enhance its affinity for uranium from wastewater
(Chen et al. 2014). Additional factors include contact time,
solution pH, the ratio of solid to liquid, and the initial metal
ion concentration in the contaminated samples (Chen et al.
2014).
Applications in biomedicine
Potential synthesizers of plant secondary metabolites
Plants are a major source of natural drugs, and are often
termed Bmedicinal^ (Venugopalan and Srivastava 2015).
However, slow growth, low amounts of drug yield, and often
time-consuming extraction processes involved in the use of
medicinal plants have led to a sharp decrease or even the
extinction of some rare plants due to over-harvesting (Huang
et al. 2014). In some instances, endophytic microorganisms
have been shown to exhibit capabilities to produce related
plant secondary metabolites, some of which have established
therapeutic value and/or other human health/cosmetic poten-
tial (Budhiraja et al. 2013; Kaushik et al. 2014). Such fungal
endophytes have been proposed to be exploited as a means to
Appl Microbiol Biotechnol
produce valuable products (Kaushik et al. 2014). Overall, the
cultivation of endophytic fungi as production systems for
valuable metabolites has many advantages over plants as
large-scale production benefits including faster growing
speeds, the reduced space, and ease of modification are evi-
dent (Palem et al. 2015). A summary of currently reported
functional compounds derived from endophytic fungi is given
(Table 1).
Anticancer compounds Taxol, camptothecin, vinblastine, and
vincristine are among the best characterized anticancer drugs
currently available. Taxol, a diterpenoid anticancer drug, is
widely used in clinical practice to target a variety of tumors
including breast and ovarian (Kusari et al. 2014).
Camptothecin (CPT) is a monoterpenoid indole alkaloid that
possesses the ability to inhibit DNA topoisomerase I (Kusari
et al. 2011). CPT and its derivatives are applied as anticancer
agents targeting small lung and refractory ovarian cancers (Pu
et al. 2013). Vinblastine and vincristine, are known as Bvinca^
alkaloids, and have been widely used in the treatment of a
variety of solid tumors, leukemia, and Hodgkin’s disease
(Palem et al. 2015). These chemicals have originally been
extracted from specific plants, e.g., taxol from Taxus brevifolia
and CPT from Camptotheca acuminata. However, since the
discovery of the taxol-producing fungal endophyte,
Taxomyces andreanae, this organism and other endophytes
are actively being developed as alternative means for the pro-
duction of Bplant-like^ secondary metabolites. Several endo-
phytic fungi belonging to different fungal genera from differ-
ent orders have been reported to produce plant secondary me-
tabolites. These include orders of Hypocreales, Eurotiales,
Polyporales, Pleosporales, Diaporthales, Capnodiales,
Botryosphaeriales, Glomerellales, and Xylariales, with new
endophytic fungi added to the list each year. However, a con-
tinued obstacle in the use of these fungi includes unstable
yields, due to lack of knowledge concerning how the produc-
tion of these metabolites is regulated and the conditions in
which optimally stimulate their production (Palem et al.
2015; Pu et al. 2013; Xiong et al. 2013).
Antimicrobial compounds In addition to producing anticancer
compounds, endophytic fungi are also a potential source of
novel antimicrobial chemicals. For example, sanguinarine is a
compound with antibacterial, anti-inflammatory, and anthel-
mintic properties that originated from Macleaya cordata
(plume poppy), Sanguinaria canadensis (bloodroot), and
Chelidonium majus (swallowwort poppy). The endophytic
fungi Fusarium proliferatum from M. cordata produced
sanguinarine when grown in potato dextrose liquid medium
(Wang et al. 2014). Rhein, usually found in Rheum palmatum
L. (the Chinese rhubarb), has good antimicrobial, as well as
antitumor, anti-inflammatory, anticancer, and hemostatic
properties (You et al. 2013). An endophytic fungus, identified
as Fusarium solani, and isolated from Rheum palmatum L.,
has been reported to be able to produce rhein (You et al. 2013).
Chlorogenic acid is a phenolic ester of caffeic and quinic
acids, with antibacterial, antifungal, antioxidant, and antitu-
mor activities. A strain of Sordariomycete sp. isolated from
Eucommia ulmoides Oliver (Du-Zhong) showed good capa-
bility to produce authentic chlorogenic acid (Chen et al. 2010).
Kaempferol is a flavonoid extracted from methanolic and
aqueous solutions of Eupenicillium parvum, an endophytic
fungus isolated from Sinopodophyllum hexandrum
(Himalayan mayapple) (Huang et al. 2014). Azadirachtin A
and its structural analogs form a well-known class of natural
insecticides with antifeedant and insect growth-regulating
properties. The endophytic fungus E. parvum isolated from
Azadirachta indica (neem) has been shown to produce
azadirachtin A and B (Kusari et al. 2012b).
Antioxidant compounds Many endophytic fungi produced
polyphenols that display antioxidant activities. For example,
endophytes isolated from the bulbs of Fritillaria unibracteata
(Anzi-Beimu in Chinese) were able to produce the antioxi-
dants gallic acid, rutin, and phlorizin in culture broth outside
the plant host (Pan et al. 2017). Several endophytic fungi have
also been shown to produce compounds equivalent and/or
identical to plant essential oils, e.g., agarwood oil originally
identified in the agarwood (Aquilaria sp.) trees, but capable of
being produced by various fungi. Agarwood oil is an example
of a high-value essential oil, due to its distinct aroma resulting
from the odoriferous properties of various terpenes present in
the plant. Studies have revealed that fungi including four
Arthrinium sp., two Colletotrichum sp., and Diaporthe sp.
from Aquilaria subintegra (lign aloes) could produce a broad
spectrum of volatile compounds, including β-agarofuran, α-
agarofuran, δ-eudesmol, oxo-agarospirol, and β-dihydro
agarofuran, compounds that highly resemble agarwood oil
originating from the plant host (Monggoot et al. 2017).
Other compounds Some endophytic fungi can produce
pinoresinol diglucoside, an important antihypertensive com-
pound found in E. ulmoides. The endophytic fungus
Phomopsis sp. isolated from E. ulmoides possesses the ability
t o pr o du c e p i n o r e s i n o l di gl u co s i d e , pi n or e s i no l
monoglucoside, and pinoresinol independent of the plant
when cultured in vitro (Shi et al. 2012; Yan et al. 2015). An
endophytic fungus from Gymnema sylvestre (gymnema) has
been shown to be able to produce gymnemagenin, which is
used as an antidiabetic agent (Parthasarathy and Sathiyabama
2014). Some endophytic fungi of Fusarium tricinctum and A.
alternata isolated from Solanum nigrum (black nightshade),
Crocus sativus (saffron), and Brassica napus (oilseed rape)
have been shown to be able to produce the plant growth-
promoting phytohormone, IAA (Khan et al. 2015a; Shi et al.
2017). Based on these and other work, it is generally

Table 1 Functional metabolites produced by endophytic fungi
Metabolite type Endophyte fungus
Camptothecin (CPT) Trichoderma atroviride
Aspergillus sp.
Fusarium solani
Fomitopsis sp.
9-Methoxy CPT Alternaria alternata
10-Hydroxy CPT Phomopsis sp.
Taxol Cladosporium cladosporioides
Paraconiothyrium SSM001
Guignardia mangiferae
Fusarium proliferatum
Colletotrichum gloeosporioides
Vinblastine Nigrospora sphaerica
Talaromyces radicus
Vincristine Talaromyces radicus
Sanguinarine Fusarium proliferatum
Rhein Fusarium solani
Podophyllotoxin Phialocephala fortinii
Chlorogenic acid Sordariomycete sp. B5
Azadirachtin A and B Eupenicillium parvum
Kaempferol Mucorfragilis fresen.
Gallic acid Fusarium sp. JZ-Z6
Fusarium sp. JZ-Z7
Rutin Fusarium redolens Sz1_1 H
Fusarium tricinctum WS11790
Phlorizin Fusarium redolens Sz1_1 H
oxo-Agarospirol Arthrinium sp. 0042
Colletotrichum sp. 0047/0048
Diaporthe sp. 0051
β-Agarofuran Colletotrichum sp. 0048
Diaporthe sp. 0051
α-Agarofuran Arthrinium sp. 0042
Colletotrichum sp. 0047
Diaporthe sp. 0051
β-Dihydro agarofuran Arthrinium sp. 0042
Colletotrichum sp. 0047/0048
Diaporthe sp. 0051
δ-Eudesmol Arthrinium sp. 0042
Diaporthe sp. 0051
Gymnemagenin Penicillium oxalicum
Pinoresinol diglucoside Phomopsis sp. XP-8
Pinoresinol monoglucoside Phomopsis sp. XP-8
Pinoresinol Phomopsis sp. XP-8
Indole-3-acetic acid (IAA) Alternaria sp.
Some endophytes
Fusariumtricinctum RSF-4L
Alternaria
alternata RSF-6L
Fusariumtricinctum RSF-4L
Al-ternaria alternata RSF-6L
B–^ represents no data available
recognized that endophytic fungi represent a largely untapped
source of novel chemical compounds that can have significant
biomedical and biotechnological applications. The
Host
Camptotheca acuminata
Miquelia dentata
Taxus media
Yew trees (Taxus)
Taxus x media
Catharanthus roseus
Catharanthus roseus
Catharanthus roseus
Macleaya cordata
Rheum palmatum L.
Podophyllum peltatum
Eucommia ulmoides Oliver
Azadirachta indica
Sinopodophyllum hexandrum
Fritillaria unibracteata
Aquilaria subintegra
Gymnema sylvestre
Eucommia ulmoides Oliver
Eucommia ulmoides Oliver
Eucommia ulmoides Oliver
Brassica napus
Crocus sativus Linn.
Solanum nigrum
Solanum nigrum
Solanum nigrum
exploration of such metabolites derived from endophytic fun-
gi remains in its infancy. With the discovery of new endo-
phytes isolated from special, including extreme environments,
Appl Microbiol Biotechnol
Biological activities References
Anticancer Pu et al. (2013)
Antineoplastic Pu et al. (2013)
Anticancer Kusari et al. (2011)
Anticancer Shweta et al. (2013)
Anticancer
Anticancer
Anticancer Zhang et al. (2009)
Anticancer Soliman and Raizada (2013);
Soliman et al. (2015)
Fungicide Xiong et al. (2013)
Anticancer Ayob et al. (2017)
Anticancer Palem et al. (2015)
Anticancer Palem et al. (2015)
Antibacterial Wang et al. (2014)
Anti-inflammatory
Anthelmintic
Antimicrobial You et al. (2013)
Antitumor
Anti-inflammatoryl
Anticancer precursor Eyberger et al. (2006)
Inflammatory disease
Antibacterial Chen et al. (2010)
Antioxidant Antitumor
Antifungal
Insecticides Kusari et al. (2012b)
Antimicrobial Huang et al. (2014)
Antioxidant Pan et al. (2017)
Antioxidant Pan et al. (2017)
Antioxidant Pan et al. (2017)
Antioxidant Monggoot et al. (2017)
Antioxidant Monggoot et al. (2017)
Antioxidant Monggoot et al. (2017)
Antioxidant Monggoot et al. (2017)
Antioxidant Monggoot et al. (2017)
Antidiabetic Parthasarathy and Sathiyabama
(2014)
Antihypertensive Shi et al. (2012)
– Yan et al. (2015)
– Yan et al. (2015)
Growth-promoting Shi et al. (2017)
Wani et al. (2016)
Khan et al. (2015a)
Khan et al. (2017)
Khan et al. (2017)
Appl Microbiol Biotechnol
and the development of effective biotechnological tools for
their characterization, endophytic fungi are attractive targets
for natural product discovery.
Biosynthesis of functional polysaccharides
Beyond medical secondary metabolites, endophytic fungi can
also produce or excrete functional polysaccharides that play
important roles in plant-endophyte interactions and exhibit
potential human health-related biological functioning, includ-
ing antioxidant, antitumor, anti-inflammatory, and antiallergic
activities, with potential applications as nutraceuticals and/or
in the pharmaceutical industry (Liu et al. 2017). In plants,
these fungal-derived polysaccharides may help the endophyte
to resist abiotic stress, assist in the formation biofilms that may
help in plant colonization, act as bioelicitors to stimulate func-
tional metabolite accumulation in their host plants, and/or ex-
ert antioxidant and other biological activities (Liu et al. 2017).
In terms of biotechnological applications, some of these mi-
crobial polysaccharides, such as dextran, xanthan, pullulan,
and hyaluronic acid, are being used as bioproducts in various
applications, e.g., coverings in wound shock control, as thick-
eners and/or suspension stabilizers, for tablet granulation and
coating, in chronic wound healing, and in eye surgeries
(Freitas et al. 2011; Moscovici 2015).
A growing number of reports indicate that endophytic fun-
gi are excellent producers of various exopolysaccharides
(EPS). The endophytic fungi Berkleasmium sp. Dzf12 from
Dioscorea zingiberensis (yellow ginger) and F. solani SD5
from Alstonia scholaris (devil tree) can produce EPS that dis-
play high antioxidant activities (Li 2012; Mahapatra and
Banerjee 2013a). A Diaporthe sp. isolated from the medicinal
plant Piper hispidum Sw has been shown to produce EPSs in
submerged cultures that showed promising antiproliferative
activity against human breast carcinoma (MCF-7) and hepa-
tocellular carcinoma (HepG2-C3A) cells (Orlandelli et al.
2017). Several EPSs produced by endophytic fungi have also
been shown to possess anti-inflammatory, antiallergic, and
antiproliferative activities. These include rhamnogalactan pro-
duced by F. solani SD5 isolated from A. scholaris (Mahapatra
and Banerjee 2012).
The biological activity of polysaccharides is closely related
to their chemical structure, which is characterized by their
molecular weights, glycosidic linkages, branching patterns,
and differences in monosaccharide compositions, and can in-
clude polysaccharide protein and/or peptide linkages (Ferreira
et al. 2015; Moradali et al. 2007). The presence of a main
chain of (1→3)-β-glucopyranose in the β-glucan (more or
less substituted at O-6 positions) might be the critical structure
for inhibitory activity in the antiproliferative activity test
(Orlandelli et al. 2017). Furthermore, 1,3-β-glucan structures
or β-glucan-protein complexes have generally been thought
to be involved in the antitumor effects of EPSs (Khan et al.
2015b). The molecular weights, biological activities, mono-
saccharide compositions, and yields of EPS production by
different endophytes are summarized in Table 2.
Biosynthesis of nanoparticles
Nanotechnology is a multidisciplinary field of applied science
that includes fabrication of devices and applications in drug
dosage with capabilities of working within physical size
ranges from 1 to 100 nm (Namdari et al. 2017), parameters
widely used in a variety of biomedical and pharmaceutical
applications (Kanamala et al. 2016; Zhao et al. 2013b).
Currently, most chemical methods used for the synthesis of
nanoparticles (Nps) are expensive, toxic, complex, and energy
intensive (Golinska et al. 2016). To overcome this problem,
endophytes have been suggested as novel Bbiofactories^ ca-
pable of synthesizing various noble metal nanoparticles
(Golinska et al. 2016). It has been claimed that synthesis using
endophytes is more efficient than use of other common mi-
crobes, since endophytes can produce highly bioactive sec-
ondary metabolites (Devi and Joshi 2015).
Synthesis of nanoparticles (mainly AgNPs) by endophytic
fungi and the antimicrobial activity of these particles versus
bacterial and fungal pathogens of humans and plants has been
extensively studied (Table 3). Endophytic fungi have been
shown to be able to synthesize nanoparticles of various sizes
(Devi and Joshi 2015; Manjunath et al. 2017; Uddandarao and
Balakrishnan 2017). For example, the endophytic fungus
Guignardia mangiferae (isolated from the leaves of medicinal
plants) can synthesize 5–30-nm-sized, spherical-shaped
AgNps (Balakumaran et al. 2015). The large variations in size
and shape among synthesized silver nanoparticles from differ-
ent endophytes might be due to the complex interaction of
intrinsic microbial metabolic complexes. Interaction of metal
ions and the enzymes (mainly reductases) occurs resulting in
the subsequent formation of nanoparticles in solution
(González-Rodríguez et al. 2012). The Bbioformed^ nanopar-
ticles appear to display broad spectrum antibacterial activity
against gram-negative and gram-positive bacteria (Golinska et
al. 2016; Raheman et al. 2011), as well as exert antifungal
activity against a number of plant pathogens (Elmoslamy et
al. 2017). The efficacy of AgNps antimicrobial activity can be
increased by combination with antibiotics, e.g., AgNp synthe-
sized by Pestalotia sp. (isolated from leaves of Syzygium
cumini) and antibiotics such as gentamycin and
sulphamethizole used together to inhibit growth of the human
pathogens Staphylococcus aureus and Salmonella typhi
(Raheman et al. 2011). Based on their strong antibacterial
activity, AgNps have been further used as nanosilver coatings
on textiles and implants, useful in the treatment of wounds and
burns, and as water disinfectant and/or room spray (Chen and
Schluesener 2008).
 Appl Microbiol Biotechnol

Mahapatra and Banerjee (2012, 2013b)

Applications in energy and biocatalysts

Mahapatra and Banerjee (2016)

Biosynthesis of biofuel

Orlandelli et al. (2017)

Li et al. (2012b, 2011)
Soaring demand for fuels and environmental problems
caused by greenhouse gas emissions have created a com-

Chen et al. (2011)

Chen et al. (2011)

Guo et al. (2014)

Yeh et al. (2014)

Yan et al. (2014)
Li et al. (2012c)

pelling need for new sustainable alternative energy sources

(Wu et al. 2017). Several reports have shown that endo-
References

phytic fungi could produce volatile organic compounds

(VOCs) while growing on plant and agricultural residues.
These VOCs are mainly hydrocarbons and other oxygenat-
ed compounds with properties that resemble fossil fuels,
2.276 ± 0.032

4.320 ± 0.022
Yields (g/L)

and have been termed Bmycodiesel,^ and are being consid-

1.329 ± 23
ered as promising alternatives to fossil fuels (Strobel et al.
13.97
Molecular weights, biological activity, monosaccharide compositions, and yields of extracellular polysaccharides by different endophytes

0.12
0.27

0.04

0.03
0.04

0.02

0.12
0.02

2008; Wu et al. 2016). For example, the endophytic fungus

–

Gliocladium roseum NRRL 50072 (later identified as

Galactose/glucose/mannose = 2:1.5:1

Galactose/glucose/mannose = 3:1:1.5

Ascocoryne sp.) has been shown to produce a series of vol-

atile hydrocarbons and their derivatives on oatmeal-based
Mannose/galactose = 2.16:1.00

Galactose/glucose = 50.6:49.4
Monosaccharide composition

Mannose/glucose = 89.4:10.6

agar and cellulose-based media in a species-specific man-

Mannose/glucose = 97.7:2.3
Galactose/rhamnose = 2:1

ner (Strobel et al. 2008; Griffin et al. 2010). Some strains of

Penicillium brasillianum, Penicillium griseoroseum,
(mol% or mole ratio)

Xylaria sp. (NICl3), Xylaria sp. (NICL5), Penicillium sp.

99% Galactose

99% Galactose

(PAOE), and various species of Trichoderma produce high

Only glucose

concentrations of a lipid matrix that may serve as promising

sources of biofuel precursors (Santosfo et al. 2011).
Another endophytic fungus, Nigrograna mackinnonii, pro-
–
–

duces a series of volatile natural products, including ter-

Anti-inflammatory

penes and odd chain polyenesseveral, which can exemplify

Biological activity

Antiproliferative

Antiproliferative

the potential of endophytic fungi in biofuel production.

Anti-allergic
Antioxidant
Antioxidant

Antioxidant

Based on the metabolic labeling and genomic analyses,

the biosynthetic pathway for some of these compounds
was found to be derived from activities mediated by a poly-
–
–

–
–
–
–

ketide synthase (PKS) followed by a decarboxylation reac-

tion (Shaw et al. 2015).
Molecular weight

8 × 103~1.4 × 104

5.9–1600 × 103

Due to the relationship between endophytes and plants,

endophytic fungi can produce lignocellulolytic enzymes that
1.87 × 105

46.6 × 103

39.4 × 103
1.5 × 104

5.2 × 106

5.2 × 105
2.9 × 104

3.6 × 104
~ 2 × 105
6 × 103

can degrade and convert plant cellulose to mycodiesel under

(Da)

microaerophilic conditions (Suryanarayanan et al. 2012).

–

These two properties indicate that these strains may be useful

Exopolysaccharide

in consolidated bioprocessing (CBP) approaches used in bio-

fuel production (Wu et al. 2017). Four endophytic fungi
(Hypoxylon sp., Hypoxylon sp., Hypoxylon sp., and Daldinia
EPS-SD1
EPS-PD1
EPS-SD2
EPS-PD2

eschscholzii) were analyzed as sources of biomass-

As1-1
As2-1

AW1
WPS

EP-I

FO1
PS-I
EPS

EPS

deconstructing carbohydrate-active enzymes, with data indi-

cating that they were promising candidates for conversion of
B–^ represents no data available

lignocellulose into advanced biofuels (Wu et al. 2017). An

Fusarium oxysporum Y24-2
Fusarium oxysporum Dzf17

Hypocreales sp. NCHU01

endophytic fungus belonging to the genus Gliocladium was

Diaporthe sp. JF766998

Diaporthe sp. JF767007

Berkleasmium sp. Dzf12

Pestalotiopsis sp. BC55

Aspergillus ochraceus
Fusarium solani SD5

able to degrade plant cellulose and synthesize complex hydro-

Aspergillus sp. Y16
Endophytic fungi

carbons under microaerophilic conditions. This fungus had

the ability to produce hydrocarbons ranging from C6 to C19
(i.e., hexane, heptane, as well as benzene) directly from cellu-
Table 2

losic biomass without the requirement for hydrolytic pretreat-

ments (Ahamed and Ahring 2011).
Appl Microbiol Biotechnol

Table 3 Biosynthesis of different nanoparticles by endophytic fungi

Endophyte fungus Host NPs synthesized Biological activities References

Aspergillus versicolor ENT7 Centella asiatica AgNPs Antibacterial Reddy et al. (2016)
Antifungal
Antioxidant
Aspergillus flavus Nothapodytes foetida ZnS NPs – Uddandarao and Balakrishnan (2017)
Aspergillus tamarii PFL2 Potentilla fulgens L. AgNPs – Devi and Joshi (2015)
Aspergillus niger PFR6
Penicllium ochrochloron PFR8
Cryptosporiopsis ericae PS4 Potentilla fulgens L. AgNPs Antimicrobial Devi and Joshi (2014)
Penicillium sp. Curcuma longa (turmeric) AgNps Antibacterial Singh et al. (2013, 2014)
Penicillium sp. Calophyllum apetalum AgNPs – Chandrappa et al. (2016)
Pestalotiopsis microspora VJ1/VS1 Gymnema sylvestre AgNPs Antioxidant Anticancer Netala et al. (2016)
Pestalotia sp. Syzygium cumini (L) AgNPs Antibacterial activity Raheman et al. (2011)
Cladosporium cladosporioides Sargassumwightii AuNPs Antioxidant Manjunath et al. (2017)
Antimicrobial
Alternaria sp. Raphanus sativus AgNPs. Antibacterial Singh et al. (2017)
Guignardia mangiferae Citrus sp. AgNPs Antibacterial Balakumaran et al. (2015)
Antifungal
Antiproliferative
Epicoccum nigrum Phellodendron amurense AgNPs Antifungal Qian et al. (2013)
Trichoderma harzianum SYA.F4 Tomato plant parts AgNPs Antifungal Elmoslamy et al. (2017)

B–^ represents no data available

Biosynthesis of biocatalysts
Given that endophytic fungi have to infect and reside in plants
without causing overt symptoms, it is possible that fungal
endophytes gather nutrients not only from the plant but also
from other sources and hence may secrete a battery of en-
zymes to catabolize complex organic polymers from the sur-
rounding environment (Suryanarayanan et al. 2012;
Thirunavukkarasu et al. 2015). For example, endophytic fungi
isolated from trees of moist deciduous and semi-evergreen
forests of India have been reported to produce glutaminase
free L-asparaginase, which has been used for the treatment
of acute lymphoblastic leukemia in adults and children
(Nagarajan et al. 2014). Endophytic fungi have the ability to
produce chitin-modifying enzymes (e.g., chitinases, chitin
deactylases, and chitosonases) presumably to restructure their
cell walls during growth and plant infection, but that can po-
tentially be exploited for biotechnological purposes
(Suryanarayanan et al. 2012). For example, 31 fungal endo-
phytes isolated from leaves of various tree species in the for-
ests of Western Ghats (southern India) exhibited positive ac-
tivity for chitinase, with different isoforms of enzyme activity
described. Many isolates produced chitosanases that act on
chitosan modified with different degrees of acetylation
(Rajulu et al. 2011). Compared with crustacean chitosans,
the fungal enzymes are typically of lower molecular weight,
have higher polydispersity, and act on substrates containing a
lower degree of acetylation (Nwe et al. 2009). Therefore,
analyzing and screening for the diversity of isoenzymes and
for the oligomers produced by these enzymes is a novel but
promising approach, as these compounds are useful in a vari-
ety of applications, e.g., food and environmental industries.
Due to the diversity of host plants that grow in a given
habitat, endophytic fungi possess a remarkable ability to adapt
to a wide range of environments (Li et al. 2012a). Endophytic
fungi (e.g., Colletotrichum sp., Paecilomyces sp., Phoma sp.,
Phomopsis sp., and Phyllosticta sp.) isolated from tannin-rich
mangrove leaves are able to grow on tannic acid-amended
medium. Wide-ranging industrial applications necessitate the
use of enzymes with different properties; thus, an increasing
appreciation exists for fungal endophytes as sources of specif-
ic and efficient biocatalysts (Suryanarayanan et al. 2012).
Current bottlenecks
Bioprocess development and scale-up
Although production and isolation of secondary metabolites
can sometimes be successful in small-scale laboratory condi-
tions, attempts at using endophytic fungi in scale-up produc-
tion of metabolites have met with poor yields and perfor-
mance. For example, the scale-up of processes for the biosyn-
thesis of functional polysaccharides is challenging because
many factors must be taken into consideration. These include
the fermenter’s apparent viscosity, solubility of oxygen,

temperature variation, cultivation times, temperature, pH, and
other factors. In addition, as the physical distance between the
impellers and vessel walls increase with reactor volume, the
heterogeneities of EPS fermentation broth occur. In order to
reach high EPS yields with the required purity and properties,
the culture parameters of the scale-up production processes
should be optimized and under controlled. Regarding the ap-
plication of VOC-producing endophytic fungi, some studies
have reported that inefficient energy supply during cellulose
degradation in fungi diminishes further growth of the producer
strains and production rates in microaerophilic conditions,
suggesting that industrial scale-up would be difficult to ac-
complish (Stadler and Schulz 2009).
Negative effects in the applications
In the application of endophytic fungi as biocontrol agents to
resist pathogenic invaders, some negative effects exist despite
many benefits. For example, endophytes isolated from the
corms of Crocus sativus (saffron crocus) can cause corm rot
in the host at different levels both in vitro and in vivo. Another
evidence is that inoculation with fungal endophyte
Cryptosporiopsis sp. can decrease and retard root growth of
its host (Norway spruce seedlings) (Terhonen et al. 2016;
Wani et al. 2016). This suggests that boundaries between an
organism acting as either a mutualist or pathogen towards the
same plant are adaptable (Zamioudis and Pieterse 2012).
Thus, many endophytes have been considered to be latent
pathogens (Kusari et al. 2012a), that can cause disease in hosts
under certain circumstances or environmental conditions
(Eaton et al. 2011). Triggers that might lead to pathogenesis
include fungal stress-activated mitogen-activated protein ki-
nases (e.g., sakA) that play essential roles in the establishment
and maintenance of the mutualistic interaction (Eaton et al.
2011). To avoid such negative effects and improve the appli-
cation of endophytes in biocontrol of plant pathogens, addi-
tional research is needed to understand the factors and risks
involved.
Regarding the application of AgNPs in biomedicine and
diagnostic fields, it is important to determine any toxicity to-
wards both normal cell lines and target cancer cell lines. Non-
specific cell toxicity of AgNPs can limit their therapeutic ap-
plications. The endophytic fungus, Pestalotiopsis microspora,
isolated from the leaves of G. sylvestre has been used to syn-
thesize various AgNPs. However, the authors show that the
cell viability of normal cells (e.g., Chinese hamster ovary) was
decreased with an increasing concentration of AgNPs, and the
IC50 value of the AgNPs against Bnormal^ cells was deter-
mined to be 438.53 ± 4.2 μg/mL (Netala et al. 2016).
Another endophytic fungus (G. mangiferae) isolated from
the leaves of medicinal plants has also been used to synthesize
AgNPs. Again, cell viability of normal African monkey kid-
ney cells decreased with increasing concentration of AgNPs,
Appl Microbiol Biotechnol
and the IC50 value was determined to be 63.37 μg/mL for the
silver nanoparticles (Balakumaran et al. 2015). Overall, how-
ever, there is only limited data available examining the cyto-
toxic effects of nanoparticles synthesized by endophytic fungi
against normal cell lines versus cancer cell lines.
Strategies for the enhancement of bioproduct
production by endophytes
To obtain valuable secondary metabolites on an industrial
scale, various strategies for improving yield and productivity
have been proposed. Current approaches are focused on ge-
netic engineering, process optimization, and co-culture fer-
mentation (Fig. 4).
Genetic engineering
A number of studies regarding bioproducts derived from
taxol-producing endophytic fungi have used genetic engineer-
ing approaches, including random mutagenesis combined
with genome shuffling and gene overexpression to enhance
or modulate expression of the desired metabolite (Ahamed
and Ahring 2011; Elgendy et al. 2016). Mutagenesis can be
employed on fungal endophytes to induce changes in the ge-
netic characteristics of organism to enhance metabolite yields,
followed by either random screening or rational screening for
improved mutants (Venugopalan and Srivastava 2015). A
high taxol-producing fungus, HDF-68, was obtained by
inactivated protoplast fusion of two mutant strains, UV40-19
and UL50-6. The yield increased by 20–25% compared to
either of the parental strains (Zhao et al. 2013a). Phomopsis
sp., a fungal endophyte of mangrove plants, can produce
deacetylmycoepoxydiene (DAM), an antitumor natural prod-
uct with a novel chemical structure. Eight parental protoplasts
of Phomopsis sp. were subjected to genome shuffling and
screened for high-yield DAM-producing strains, resulting in
strains with > 200-fold yield of the desired product after two
rounds of genome shuffling (Wang et al. 2016). In the endo-
phytic fungus, Ozonium sp. EFY-21, isolated from Taxus
chinensis var. mairei (Chinese yew), overexpression of a key
enzyme gene, TS, catalyzing the first slow committed step in
taxol biosynthesis reaction, via transformation and expression
of the protein product driven by a fungal-specific promoter
resulted in ~ 5-fold increase in taxol production as compared
to the parent strain (Wei 2012).
Enhancing metabolic flux, i.e., manipulation of precursor
pools, by overexpression of downstream limiting enzymes
and/or blocking of the competing metabolic pathways, strate-
gies used in various microbial strain enhancements for other
products, is a prospective way to enhance the yield of desired
metabolites. The taxadiene-biosynthetic cluster has been
reconstituted in Escherichia coli and then used to affect the
mevalonate (MVA) pathway, after transformation into A.
Appl Microbiol Biotechnol
Fig. 4 Solutions to the enhancing
of secondary metabolite yields
alternata TPF6 to produce taxadiene. This effect overcome
obstacles encountered during the first committed step of
taxadiene production in fungi, resulting in stable production
(61.9 ± 6.3 μg/L) of taxadiene in A. alternata TPF6 (Bian et
al. 2017). Blockage of sterol biosynthesis, which is a strong
competitive pathway for taxol synthesis, has a dramatically
positive effect on taxol yield. Thus, exploitation of CRISPR/
Cas9 system or other means of genetic engineering for
targeted gene disruption that would reduce flux into unwanted
metabolitic pathways could improve the industrial production
of taxol and other secondary metabolites.
Process optimization
Optimized process parameters
Secondary metabolite production by fungi is controlled by
diverse factors, many of which are poorly understood.
Known factors include culture media composition, ratio of
nutrients, pH, aeration, temperature, and the time on cultiva-
tion (Elmoslamy et al. 2017). A diuron-degrading endophyte
identified as Neurospora intermedia DP8-1 was isolated from
sugarcane root grown in diuron-treated soil. By optimizing the
fermentation parameters (including temperature, pH, inocula-
tion size, carbon source, and initial diuron concentration),
strain DP8-1 was found to be able to degrade up to 99% of
the diuron present within 3 days (Wang et al. 2017). An en-
dophytic fungus, F. solani from Ferocactus latispinus (Devil’s
Tongue Barrel), could produce a variety of polyketides from
naphthoquinone precursors. The carbon/nitrogen ratio and pH
value found to influence polyketide production, and the opti-
mum value of total products derived from naphthoquinones
(476 μmol/L) was obtained via determination of optimized
conditions (Gracidarodríguez et al. 2017). After the optimiza-
tion, a bench-scale bioreactor was developed to check its ap-
plicability for continuous metabolite production (Bhalkar et
al. 2016a). Considering that all fungal endophytes are located
in the internal plant tissues, i.e., in the dark, light treatment has
been shown to dramatically influence taxol production in the
endophytic fungus Paraconiothyrium SSM001, with light ex-
posure resulting in decreased taxol production and a repres-
sive effect on the expression of genes involved in taxol bio-
synthesis (Soliman and Raizada 2018).
Precursor feeding and elicitor addition
Precursor feeding is a strategy of exogenously supplying bio-
synthetic precursors or other intermediates involved in the
biosynthetic pathway to the culture medium in order to in-
crease end-product yield. It has been reported that addition
of tryptamine as a precursor and bovine serum albumin as
an elicitor significantly enhanced camptothecin yields in the
endophyte F. solani isolated from Camptotheca acuminata

(up to 4.5 and 3.4-fold, respectively) (Venugopalan et al.
2016). Another study revealed that ethanol addition could also
enhance camptothecin production when added as an elicitor
and/or carbon/energy source (Aarthi and Smita 2015). In axe-
nic culture, many endophytic fungi gradually appear to atten-
uate their ability to produce various secondary metabolites.
This phenomenon could be reversed with treatment with 5-
azacytidine, a DNA methyltransferase inhibitor, indicating
that addition of some signals from plant tissue could prevent
the methylation or silencing of genes responsible for CPT
biosynthesis, and that epigenetic mechanisms are likely im-
portant means for control of secondary metabolite expression
(Vasanthakumari et al. 2015).
Studies have also indicated that isopentenyl pyrophos-
phate (IPP, isoprene) and geranylgeranyl diphosphate
(GGPP) are precursors involved in taxol biosynthesis in
Paraconiothyrium SSM001. Exogenous addition of IPP
and GGPP in the culture media could significantly enhance
the taxol production in the fungus. Furthermore, integration of
the Taxus canadensis GGPPS gene, responsible for GGPP
production, into the fungal genome, followed by inclusion in
the culture media of GGPP precursor compounds, resulted in
increased taxol production in the resultant genetically
engineered strain (Soliman et al. 2017).
Co-culture fermentation
Co-culture fermentation involves the cultivation of two or
more microorganisms in the same confined environment, po-
tentially better mimicking natural microbial communities
(Bertrand et al. 2014). The overall idea behind this method
is that some microbial secondary metabolite gene clusters may
be activated or stimulated in the presence of other microor-
ganisms. This may be especially relevant for the production of
antibiotics, i.e., the synthesis of such products is driven by
competition, but may also be important for the production of
other compounds involved in establishment and/or mainte-
nance of microbial communities. Two endophytic fungi,
Colletotrichum fructicola SUK1 and Corynespora cassiicola
SUK2, isolated from plant Nothapodytes nimmoniana (Grah.)
Mabb. (Ghanera), were able to synthesize CPT independent of
the host plant under laboratory fermentation conditions.
However, under optimized conditions, the yield from samples
in which both fungi were co-cultured was > 1.4-fold higher
than samples containing monocultures of the two fungi
(Bhalkar et al. 2016b). In studies aimed towards increasing
hydrocarbon production by the endophytic fungus, G. roseum,
co-culture of the fungus with Escherichia coli was found to
stimulate hydrocarbon production at a 100-fold higher level
than pure G. roseum cultures (Ahamed and Ahring 2011).
Based on the chemical ecology of fungal endophytes in
their plant host, these organisms may form complex relation-
ships with other endogenous microbes. Co-culture of the
Appl Microbiol Biotechnol
fungal endophyte, Paraconiothyrium SSM001, isolated from
Taxus (yew) trees with a bark fungus (Alternaria) resulted in a
3-fold increase in taxol production; moreover, when SSM001
was co-cultured with both Alternaria and another fungus,
Phomopsis, that is also present on the yew plant, there was
an 8-fold increase in taxol yield (Soliman and Raizada 2013).
These data indicate that co-resident fungi and potentially other
microbes within the host plant can interact with one another to
stimulate biosynthesis of secondary metabolites. These inter-
actions may be mediated by direct cell-cell contacts or via
their metabolites.
Conclusions
Since the discovery of various useful metabolites produced by
endophytic fungi, these organisms have been proposed as al-
ternative sources of a wide range of bioproducts. The ability of
endophytes to produce secondary metabolites is closely relat-
ed to their chemical ecology and the long-term interactions/
co-evolution they have had with their host plants. Thus, a
deeper understanding of the factors involved in mediating this
relationship is needed in order to better understand the func-
tions and production of useful metabolites. Products derived
from endophytic fungi have significant potential for use in
various applications extending from agriculture, to the envi-
ronment remediation, biomedicine, energy, and biocatalysis.
However, hurdles remain before their commercial exploitation
can be fully realized. Current bottlenecks in synthesis, scale-
up development, and potential toxicity of the products need to
be overcome in order for greater applications to occur. Current
studies are mainly focusing on enhancing metabolite yields;
however, the strategies to improve negative effects in practical
use of these products are also needed. Future studies aimed
towards uncovering mechanisms of secondary metabolite syn-
thesis and ways to manipulate these pathways for novel natu-
ral products discovery from endophytic fungi are also needed.
The significant uptapped potential of these organisms war-
rants greater attention.
Funding This study was funded by the National Natural Science
Foundation of China (grant no. 31471718, 1701722), the Modern
Agricultural Industry Technology System (CARS-30), the National Key
Technology R&D Program (2015BAD16B02), Key Research and
Development Plan of Shaanxi Province (2017ZDXL-NY-0304), the
Innovation Foundation for Doctor Dissertation of Northwestern
Polytechnical University (CX201840), and the Key Projects of
Graduate Creative Innovation Seed Funding of the Northwestern
University of Technology (Z2017059).
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
Appl Microbiol Biotechnol
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors
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