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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
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The compound was found to be effective against a variety of food-borne and food-spoilage
bacteria, including Staphylococcus aureus, Escherichia coli, Salmonella typhi, Salmonella
typhimurium, Salmonella enteritidis, Aeromonas hydrophila, Yersinia sp., Vibrio anguillarum,
Shigella sp., and V. parahaemolyticus. The authors suggested that this natural compound could
be utilized as a food preservative. Yunianto et al. (2014) identified the endophytic fungus
Penicillium sp. from the Srikaya plant (Annona squamosa L.), which produced very potent
antibacterial bioactive agents meleargrine and chrysogine.
FIGURE 11.1 Selected commercially available treatment agents produced by endophytic microorganisms.
In a detailed study carried out at Santiniketan, endophytic Alternaria alternate was
isolated from mature and healthy Azadirachta indica leaves. Bacillus subtilis MTCC 121,
Listeria monocytogenes MTCC 657, S. aureus MTCC 96, Staphylococcus epidermidis
MTCC 2639, and S. typhimurium MTCC 2639 were all strongly susceptible to the fungal
extracts (Chatterjee et al., 2019). Rivail et al. (2018) studied the antimicrobial properties of
⏎
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Rhizophora mucronata endophytic fungi, and extracts from 14 strains (64.3%) displayed
action against S. aureus, E. coli, and Candida albicans. Cladosporium sp. from Thespesia
populneoides and Xylaria sp. from Acanthus ilicifolius were shown to inhibit B. subtilis,
Pseudomonas aeruginosa, E. coli, and S. aureus. Similarly, in a more recent investigation
by Zhou et al. (2022), 32 extracts (69.6%) of the 46 endophytic fungal strains tested positive for antibiotic activity against Enterococcus faecalis and methicillin-resistant S. aur eus
(MRSA).
11.4.2 ANTIFUNGAL AGENTS
Endophytic microorganisms are a source of antifungal agents, which are molecules that
can selectively target and kill fungi. Several fungal endophytes have been reported to
synthesize antifungal agents, such as griseofulvin and amphotericin B, which are used in
the treatment of fungal infections. Jesterone is a naturally occurring antifungal chemical
discovered from the fungus Pestalotiopsis jester (Li and Strobel, 2001). Pestaloside, an
aromatic β-glucoside, and two pyrones, pestalopyrone and hydroxypestalopyrone, were
isolated from the fungus P. microspora, are reported as antifungal agents. This fungus was
isolated from the plant Torreya taxifolia
(Lee et al., 1995). Altomare et al. (2000) isolated
two alpha pyrone compounds from Fusarium semitectum; namely, fusapyrone and deoxyfusapyrone, that exhibit high antifungal activity against a variety of pathogenic or mycotoxogenic filamentous fungi: Aspergillus flayus, Botrytis cinerea, Alternari aalternata,
Cladosporum cucumerinum, Phoma tracheiphila, and Penicillium verrucosum. Culture
extract of Pestalotiopsis guepinii, Phomopsis sp., and Guignardia sp. showed very active
antifungal activity against Saccharomyces cerevisiae, Geotrichum sp., Cladosporium
elatum, Mycotypha sp., Penicillium canadensis (Rodrigues et al., 2000). In a more recent
study, two new polyketides with an extraordinary “C12–C6” carbon skeleton have been
produced by endophytic Phomopsis sp. These compounds were observed to suppress the
activity of Bipolaris sorokinian, Alternaria alternata, Fusarium avenaceum, and Bipolaris
sorokiniana (Ma et al., 2020).
11.4.3 ANTIMALARIAL AGENTS
Malaria is still one of the world’s major causes of death and morbidity, with over 3.3 billion
people at risk of infection (Ateba et al., 2018). Endophytic fungi products munumbicins E-4
and E-5 were found to have an antimalarial activity that was twice as effective as chloroquine
(Suryanarayanan et al., 2003). Diaporthemiriciae, an endophyte, was discovered to produce
epoxy cytochalasin H, an SM with significant antimalarial action against Plasmodium
falciparum chloroquine-resistant strain (Ferreira et al., 2017). Endophytic species Paecilomyces
lilacinus and P. janthinellum
, according to Ateba et al. (2018), are a source of new compounds
active against P . falciparum and potentially useful in the treatment of malaria. Endophytic fungi
such as Fusarium sp. and Nigrospora sp. have also been reported to secrete antiplasmodial
compounds specifically against P. falciparum
(Kaushik et al., 2014).
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11.4.4 ANTIVIRAL AGENTS
Endophytic microorganisms have also been shown to produce compounds with antiviral
properties, which can inhibit the replication of viruses. These compounds are of great
interest due to the increasing prevalence of viral infections worldwide. Examples of antiviral
compounds produced by endophytic microorganisms include acyclovir, ganciclovir, and
ribavirin. As a unique therapeutic technique, the use of endophytes as a source of antiviral
medicines has garnered attention. Endophytes produce antiviral compounds in response to
the biotic stress caused by the virus inside the host. For instance, novel cytogenic acids A
and B synthesized by the fungal endophyte Cytonaema sp. inhibited human cytomegalovirus
(hCMV) protease (Guo et al., 2008), while hinnuloquinone produced by Nodulisporium
hinnuleum, an endophyte of Quercus coccifera, inhibited the human immunodeficiency
virus type-1 (HIV -1) protease (Singh et al., 2004). Emerimidine A and B from the endophyte
Emericella sp. displayed significant action against influenza virus H1N1 (Zhang et al., 2011),
and 7-dehydroxyl-zinniol from Alternaria solani showed moderate activity against hepatitis
B virus (Ai et al., 2012). Altertoxins, including altertoxin I, II, III, and IV, produced by
Alternaria tenuissima from Quercus emoryi, inhibited HIV virus at various concentrations
(Bashyal et al., 2014). Additionally, alternariol and alternariol-9-methyl ether from A.
alternate isolated from Punica granatum demonstrated powerful anti-HCV NS3/4a protease
activity (El-Kassem et al., 2019).
11.4.5 ANTICANCER AGENTS
Endophytic microorganisms have been a rich source of anticancer agents, which are molecules that can selectively target and kill cancer cells. In recent times, fungal endophytes
have gained lots of scientific attraction as a result of their ability to synthesize several
varieties of anticancer agents such as taxol, podophyllotoxin, vinca alkaloids, graphislactone A, rohitukin, cytochalasin 1-3, fusarithioamide A, and malformin E (Rai et al., 2021).
Anticancer compounds produced by endophytic fungi include alkaloids, polyketides,
depsipeptides, ergochromes, sesquiterpenes, chromones, aldehydes, quinones, depsidones,
esters, lignans, diterpenes, cyclohexanones, and xanthones (Li et al., 2018).
Taxomyces andreanae, a fungal endophyte from Taxus brevifolia, has been shown to
produce the anticancer bioactive compound paclitaxel, dubbed the “golden” compound
that has rekindled optimism in the search for new anticancer agents (Manganyi and Ateba,
2020). Taxol and its related compounds have also been isolated from a wide range of
endophytes, including Grammothele lineata (Das et al., 2017), Aspergillus aculeatinus
(Qiao et al., 2020), Alternaria brassicicola (Gill and Vasundhara, 2019), Collectotrichum,
Fusarium, and Acremonium species from a Taxus baccata that has been altered
ecologically (El-Bialy and El-Bastawisy, 2020). Pestalotiopsis microspora, Alternaria
alternata, Periconia sp., Pithomyces sp., Chaetomella raphigera, Monochaetia sp.,
Seimatoantlerium nepalense, Phyllosticta spinarum, and Bartalinia robillardoides have
all been also found to produce anticancer bioactive agents that are chemically related to
taxols (Tiwari and Bae, 2022). Several taxol-producing endophytes offer a less expensive
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and readily available option for anticancer agents, such as taxol that has been approved
by the Food and Drug Administration (FDA) for the treatment of advanced breast cancer,
lung cancer, and refractory ovarian cancer (Kumar et al., 2017). Given the evidence that
endophytic fungi produce a variety of metabolites with effective anticancer activities, it
is vital to focus on studies that regularly analyze the potential of fungal endophytes to
produce better anticancer natural compounds.
11.4.6 ANTIOXIDANTS
Endophytic microbes are also a source of antioxidants, which are compounds capable of
neutralizing dangerous free radicals in the body. These free radicals are created during
normal metabolic processes and have the potential to harm cells and tissues, resulting in
a variety of illnesses. Endophytic fungi are known to produce a number of antioxidant
chemicals that are responsible for host plant stress tolerance. Nwobodo
et al. (2017)
investigated the antioxidant properties of SMs obtained from endophytic fungi from the
medicinal plants Cola nitida and Garcinia kola. Similarly, in an earlier study carried out
by Suryanarayanan et al. (2009), graphislactone A, a phenolic compound produced by the
endophyte Cephalosporium species was found to exhibit better antioxidant activity than
ascorbic acid and butylated hydroxytoluene (BHT). Also, Shoeb et al. (2014) reported
the production of an antioxidant called terminatone by the endophytic fungus Penicillium
thiomii. Recently, an ethyl extract of the fungal endophyte Chaetomium nigricolor linked
with C. roseus was discovered to exhibit apoptotic, cytotoxic, and antioxidant properties
(Dhayanithy et al., 2019). There are several other documented shreds of evidence that
fungal endophytes are natural sources of antioxidant chemical substances that play critical
roles in cancer and other oxidative-related disorders. Alternaria alternata AE1, an endophytic fungus isolated from Azadirachta indica, produced SMs with very high antioxidant
activity . The SMs demonstrated antioxidant potential in 2,2-diphenyl-1-picrylhydrazyl free
radical and superoxide radical scavenging tests, with IC50 values of 38.0 and 11.38 g/mL,
respectively (Chatterjee et al., 2019). Meanwhile, an earlier study reported the discovery of
pestacin, isopestacin, and 1,3-dihydro isobenzofurans from the endophytic Pestalotiopsis
microspora isolated from Terminalia morobensis, which likewise displayed highly effec-
tive antioxidant activity (Strobel et al., 2002).
In addition to the above, endophytic microbes have also been reported to synthesize
other bioactive compounds such as plant growth-promoting substances, enzymes, and SMs.
For instance, endophytic bacteria have been shown to synthesize plant growth-promoting
compounds such as indole acetic acid and gibberellins, which can enhance plant growth
and increase crop yield (Kusari and Spiteller, 201 1). Moreover , several endophytic bacteria
have been found to produce enzymes, such as cellulases and xylanases, which are essential
in the production of biofuels and other industrial processes (Dogan and Taskin, 2021).
In summary, the identication of biologically active compounds produced by endophytic
microorganisms has opened up new opportunities for the development of new pharmaceuticals, agrochemicals, and industrial items.
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11.5 STEPWISE METHODS FOR NATURAL PRODUCT DISCOVERY FROM ENDOPHYTIC MICROORGANISMS
There are several methods for the discovery of natural products from endophytic microorganisms. This section will discuss some of the most common techniques for the isolation,
cultivation, and characterization of endophytes, as well as the extraction and purification
of natural products.
11.5.1 PLANT SELECTION RATIONALE
Understanding the methods and rationale utilized to provide the best opportunity to identify
novel endophytic microbes at the genus, species, or biotype level is critical. Precise rationale
guides the selection of plants for endophyte isolation for natural product discovery and
development. Several parameters govern the plant selection method, according to Strobel
et al. (2004), which include the following:
• The study prioritizes plants in unique ecological environments, particularly those
with distinctive biology and novel survival strategies.
• Plants with an ethnomedicinal history of usage by Indigenous people that are
relevant to the specific uses or applications of interest are also chosen. These plants
are identified by either direct interaction with locals or by reviewing local literature.
• Endophytes with active natural products are more likely to be found in endemic
plants with extraordinary longevity or that have populated specific ancient landmasses, such as Gondwana land.
• Endophytes with a high level of biodiversity are more likely to be found in plants
growing in high biodiversity settings.
11.5.2 ISOLATION AND CULTIVATION OF ENDOPHYTES
The isolation and cultivation of endophytic microorganisms is the first and crucial step in
natural product discovery . T o isolate endophytic microorganisms, plant tissues are collected
aseptically from healthy plants. The collected tissues are surface sterilized to remove any
surface contaminants and then cut into small pieces to release the endophytic microorganisms. The tissue fragments are then placed onto different growth media, which are
designed to support the growth of endophytic microorganisms. Several types of media are
used to isolate and cultivate endophytic microorganisms, including PDA, yeast mannitol
agar (YMA), and Luria–Bertani (LB) agar. The choice of the growth medium depends on
the type of endophyte being targeted for isolation.
After the isolation of endophytic microorganisms, the cultivation process can begin.
The cultivation of endophytes is done using liquid or solid media, and it typically involves
optimizing the growth conditions such as temperature, pH, and nutrient availability to
enhance the synthesis of bioactive compounds. Several techniques are used to optimize
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the growth conditions of endophytic microorganisms, including the use of bioreactors and
various types of culture media, such as shake asks and deep-well plates.
11.5.3 CHARACTERIZATION OF ENDOPHYTES
Once the endophytes have been isolated and cultivated, they can be characterized to
determine their taxonomic identity and potential for producing bioactive compounds. This
can be done using techniques such as DNA sequencing, morphological assessments, and
biochemical assays. The characterization of endophytic microorganisms is the second
step in natural product discovery. It involves identifying and classifying the endophytes
according to their morphological, biochemical, and genetic properties. The characterization
of endophytic microorganisms is essential for the successful discovery of bioactive natural
products. It aids in the identification of endophytes with the potential to produce bioactive
compounds and allows for the adjustment of growth conditions in order to increase the
synthesis of these compounds.
11.5.4 EXTRACTION OF NATURAL PRODUCTS
After the endophytes have been characterized, the next step is to extract the natural products.
This can be done using a variety of techniques such as extraction with solvent, solid-phase
extraction, and supercritical fluid extraction. The extraction and purification of natural
products from endophytic microorganisms is the third and final step in natural product
discovery. It involves separating the bioactive compounds from the complex mixture of
metabolites produced by the endophytes.
Extraction of natural products is typically done using solvents such as ethyl acetate,
methanol, ethanol, or chloroform. The choice of solvent depends on the polarity of the
target compound and its solubility in different solvents. The extraction is typically done
by maceration, which involves soaking the endophyte culture in the solvent for a given
duration to allow for the extraction of the bioactive compounds. After extraction, the
crude extract is usually fractionated to isolate the target compound. Fractionation can be
done using several techniques such as chromatography, distillation, and crystallization.
Chromatography is the most commonly used method for fractionation, and it can be done
using various chromatographic methods, such as gas chromatography (GC), thin-layer
chromatography (TLC), and high-performance liquid chromatography (HPLC).
11.5.5 PURIFICATION OF NATURAL PRODUCTS
Once the natural products have been extracted, they need to be purified to obtain a highly
pure compound. This can be done using techniques such as chromatography, crystallization, and distillation. One of the challenges in natural product discovery from endophytic
microorganisms is the low yield of bioactive compounds. Therefore, optimization of the
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growth conditions for endophytic microorganisms is crucial for increasing the yield of
bioactive compounds.
It is important to note that the methods used for natural product discovery from endophytic microorganisms involve a combination of isolation, cultivation, and characterization
of endophytes, as well as extraction and purication of natural products. These methods
are essential for nding bioactive natural compounds that could be employed in a variety
of applications.
11.6 BIOSYNTHESIS AND STRATEGIES FOR THE OPTIMIZATION OF NATURAL PRODUCT DISCOVERY FROM ENDOPHYTIC MICROORGANISMS
Previous research has revealed that SM-producing genes in microorganisms spread
throughout the genome, much like the primary metabolite-producing genes in fungi.
However, more recent research demonstrates that the biosynthetic gene clusters (BGC)
contain genes for the production of natural products, such as the polyketide synthase
(PKS) and nonribosomal peptide synthase (NRPS) found in extrachromosomal material
or plasmids of endophytic fungi that synthesize polyketides and oligopeptides with
antimicrobial properties (Mishra et al., 2017). According to a study by Keller et al. (2005),
fungi use a few precursors taken from primary metabolic pathways to help them produce
SMs. Endophytes may engage in a variety of intricate gene-level interactions with the host
plant, as suggested by their capacity to synthesize similar SMs produced by the host. In
bacteria, fungi, and other eukaryotic organisms, horizontal gene transfer is observed. This
process involves the transfer of genetic material between different organisms, and it may
help explain why endophytic microorganisms produce host-specific SMs as a result of their
millions of years of coevolution (Digra and Nonzom, 2023).
Recent research reports that endophytic fungi also use shikimic or enzymatic pathways
to synthesize SMs (Aharwal et al., 2021). However, genome sequencing has shown that the
genes in the control of producing the same SMs in the host and their associated individual
endophyte are different, suggesting that their evolution has occurred independently of their
host (Mattoo and Nonzom, 2021). For instance, the plant Taxus sp. and its endophyte T.
andreaneae both produce taxol, although neither one produced any sequence similarity to
the other when examined (Heinig et al., 2013). Similarly , Picea glauca is known to produce
a defensin molecule called endopiceasin; however, it was later discovered on two dif ferent
independent occasions that one of its endophytic fungi produced this endopiceasin initially
(Picart et al., 2012; Mygind et al., 2005). An explanation for this could mean that during
stress conditions, there may be gene cross-activation by shared precursors between the
plant and its associated endophytes, resulting in the production of bioactive compounds.
BGCs are present in insufcient amounts in endophytic fungi, yet SMs are not produced
accordingly by the fungal strains (Rashmi and Venkateswara Sarma, 2019). Several
techniques for enhancing endophytic fungi’s metabolite production in isolation from their
host have been proposed, including changing cultivation parameters, co-culturing, and
the use of epigenetic modiers and various molecular approaches (Gakuubi et al., 2021).
The discovery of natural compounds from endophytic microbes requires the development
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of efcient strategies that can maximize the chances of identifying benecial novel
compounds. Some of the strategies that have been used for natural product discovery from
endophytic microorganisms include the ones mentioned in the section that follows.
11.6.1 EXPLORATION OF NOVEL MICROBIAL SOURCES
The first step in natural product discovery from endophytic microorganisms is to isolate
and characterize novel microbial strains. This can be done by sampling different species of
plant from different geographical locations and at the same time using different isolation
techniques. For example, W en
et al. (2023) recently reported the isolation of 124 endophytic
fungi from the medicinal plant Ageratina adenophora using different isolation techniques,
leading to the discovery of several novel compounds. Similarly , Pandey et al. (2022) reported
the isolation and characterization of several species of endophytic bacteria from bryophytes
using morphological, biochemical, and 16 SrRNA approaches.
11.6.2 METABOLOMICS-GUIDED DISCOVERY
Traditional screening methods for natural products, such as bioassay-guided fractionation
and dereplication, can be time-consuming and inefficient for the discovery of novel
compounds from complex mixtures. Therefore, innovative screening methods, such as
metabolomics have been developed to fast-track natural product discovery from endophytic
microorganisms. Metabolomics is a powerful tool for identifying novel natural compounds
derived from microorganisms. This involves the analysis of all small molecules present in
a biological sample and can be used to identify new compounds based on their unique mass
and spectral characteristics. A recent study by Hussein
et al. (2022) used metabolomics to
identify a novel antibacterial compound, monomethyl sulochrin-4-sulfate, from an endophytic fungus Aspergillus fumigatus.
11.6.3 COCULTURE
Coculture, also known as cocultivation (for solid media) or mixed fermentation (for liquid
media), is the simultaneous growth of two or more strains of microbes with the purpose
of simulating the numerous complex interactions that occur when microorganisms cohabit
naturally (Selim et al., 2018). Microorganisms live in complex multispecies communities in
their natural habitats, which include members of their own population as well as members
of other populations. In sharp contrast to the primarily axenic laboratory-characterized
microbial cultivation systems, such communities exhibit complex intra- and interspecies
interactions (Stroe et al., 2020; Reen et al., 2015). Numerous studies have shown that
certain microbes need an ecological context to activate their cryptic BGCs, including inti-
mate contact with other microbes and/or host plants for plant-associated microorganisms
and even animals (Stroe et al., 2020).
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Fungus-fungus and fungus-bacterium co-culture are the two main coculture strategies
employed for the induction of cryptic BGCs in fungal endophytes (Gakuubi et al., 2021).
Paclitaxel production was tripled when the endophytic fungus Alternaria sp., was co-cultured
with Paraconiothyrium sp., a paclitaxel-producing endophytic fungus (Soliman and Raizada,
2013). Additionally, paclitaxel production further increased 7.8-fold when Phomopsis sp.,
another endophytic fungus, was added to the co-culture mixture as compared with when
Paraconiothyrium sp. was axenically cultured (Soliman and Raizada, 2013). Similarly, when
the fungal endophyte Fusarium tricinctum was co-cultivated with Streptomyces lividans TK24
on a solid rice medium, Moussa et al. (2019) discovered four new dimeric naphthoquinones
and a new lateropyrone compound, which were not present in the axenic fungal cultures.
11.6.4 GENOME MINING
The utilization of a strategy based on genome mining that makes use of technologies for gene
editing and bioinformatics analysis as well as the availability and abundance of genomic
data to locate BGCs in the microbial genome that synthesize novel natural products (Malit
et al., 2022), is a novel strategic method for acquiring novel natural products from endophytic
microbes. This approach, also known as a “bottom-up” approach, is an effective technique
for comprehending the biosynthesis of numerous natural products, and it enables the manipulation of biosynthetic pathways to enhance yield, activate silent BGCs, and express BGCs in
heterologous systems. Using genome-mining techniques, Ming et al. (2023) recently identified BCGs responsible for forty-five SMs in Dactylonectria alcacerensis CT-6. However, the
majority of these BGCs are still unidentified and require further investigation. So far, only six
compounds have been identified from D. alcacerensis CT-6 fermentation products.
11.6.5 MODULATION BY ULTRAVIOLENT IRRADIATION
Another approach for finding natural compounds from endophytic microorganisms is the
use of UV treatment. This involves exposing endophytic microorganisms to dif ferent wavelengths of UV light to induce the synthesis of novel natural compounds. UV irradiation
can be used to enhance the diversity of natural products produced by endophytic microorganisms, as well as to activate silent BGCs that are not expressed under normal growth
conditions. For instance, a recent study by Nwobodo et al. (2022b) applied the UV irradiation strategy to increase the synthesis of bioactive compounds by the fungal endophyte,
Lasiodiplodia theobromae. The researchers exposed the fungus to different wavelengths
of UV light and identified several new compounds, including a novel guanazole derivative
which has been reported to have anticancer activity.
11.7 FUTURE DIRECTIONS AND CHALLENGES
Despite the significant progress that has been made in the discovery and application of
natural products from endophytic microorganisms, there are still a number of challenges
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that must be figured out. The following are some of the potential directions and challenges
in this field:
11.7.1 IMPROVING THE EFFICIENCY AND ACCURACY OF SCREENING METHODS
The development of innovative screening methods, such as metagenomics and metabolomics,
has accelerated the discovery of natural products from endophytic microorganisms. Nevertheless, these approaches continue to confront a number of problems, including the limited
availability of reference databases and the need for advanced computational tools. Therefore,
further research is needed to improve the efficiency and accuracy of these screening methods.
11.7.2 ENHANCING THE SCALABILITY AND AFFORDABILITY OF PRODUCTION METHODS
The production of natural products from endophytic microorganisms can be challenging due
to their low yield and complex chemical structures. Therefore, it is crucial to develop scalable and affordable production methods that can meet the demand for these natural products.
11.7.3 ENSURE NATURAL PRODUCT SAFETY AND EFFICACY
Natural products derived from endophytic microorganisms must be properly examined
before being used in medicine, agriculture, or industry. As a result, it is critical to develop
stringent criteria and guidelines for the quality control and safety assessment of these
natural products.
In addition to the challenges mentioned, there are also opportunities for future research
in natural products research from endophytic microorganisms. For instance, understanding
the molecular mechanisms underlying the biosynthesis of bioactive compounds can enable
the manipulation of these pathways to enhance yield and improve the properties of these
compounds. Furthermore, the use of synthetic biology approaches to engineer endophytic
microorganisms for improved production of natural products is another promising avenue
for research.
Finally, another opportunity is the exploration of the potential of endophytic microorganisms as biological control agents for plant-associated pathogens. Studies have
demonstrated the capability of endophytic microorganisms to inhibit plant pathogens and
protect plants against diseases [38]. This could have signicant implications for sustainable
agriculture and the reduction of pesticide use.
11.8 CONCLUSIONS
Natural products derived from endophytic microorganisms have gained significant
consideration from the scientific community as a result of their unique biological