Introduction

Endophytes are microorganisms, such as bacteria, fungi, and actinomycetes, which spend all or part of their lives in plant tissues. Endophytic microorganisms are present in almost all plants where they live asymptomatically after colonizing the healthy host plant tissues. Their association is generally regarded as harmless to beneficial to the host plants. The plant–endophyte interactions can be obligate or facultative. The plant–endophyte relations can be multifaceted, though mostly mutualistic with their associated host plants [1]. Plant interactions involve intimate associations with an array of endophytic taxa that are organ specific to roots, stems, leaves, flowers, fruits, and seeds with some of them having beneficial effects on plants [2]. Endophytes can be used to produce a wide range of compounds with potential applications in modern medicine, industry, and agriculture [3]. Endophytic microorganisms showed a wide range of applications in healthcare [4], bioremediation [5], nanotechnology [6], and other industries.

Almost every plant species is thought to be associated with one or more endophytic microorganisms. About 3,000,000 plant species are known to exist on the planet; however, only a few of these plant species have been studied in depth for their corresponding endophytic biology [7]. Out of approximately one million endophytic species empirically associated with different plants worldwide only a small percentage of endophytes have been extensively researched [8].

Plants sustain and restrain endophytic growth, and endophytes, in turn, use a variety of mechanisms to develop non-disruptive changes in their living environments within the host tissue. Endophytic microorganisms have an impact on plant physiology by producing chemically diverse entities, such as hormones and secondary metabolites that can promote plant growth or modulate metabolic pathways and even gene expression in response to abiotic or biotic stress [9]. They are known to produce secondary metabolites that provide significant ecological benefits to their host plants; it has also been demonstrated that many endophytes produce potent pharmacological agents for the treatment of cancer and infectious diseases [10].

Microbes are major producers of a wide range of bioactive metabolites, with fungi at the forefront of producing metabolites with a wide range of bioactivities and applications. Extracellular enzymes produced by microbial endophytes include cellulases [11], laccases [12], pectinases, amylases [13], proteinases, and lipases. These enzymes are hydrolytic, and this process may aid in the restriction and killing of pathogens, simultaneously meeting a part of the nutritional need for the endophyte itself [13]. It is tempting to believe that the diverse range of bioactive compounds produced by endophytic microorganisms is related to the co-evolutionary changes in these microorganisms [14]. It is entirely possible that such close interaction between the endophytic cell and plant tissue allowed for some genetic exchange, in which endophytes acquired genetic material from plant species that made them more suited for dwelling and adaptation in the tissues of the inner host [15]. Furthermore, that might have enabled the fitter endophytes toward host protection against biotic and abiotic challenges.

There is an increasing demand for novel and potent compounds to treat a variety of clinical conditions. Incidences of fungal infections, emerging novel viral infections, drug resistance in bacteria, and risks associated with organ transplants all highlight our inability to deal with such emerging healthcare problems [4]. Endophytic microorganisms appear to be a potentially promising alternate resource in hand for providing potent, safe, and cost-effective natural bioactive solutions. However, more systematic investigation and study of endophytes are required to uncover their biotechnological applications and broad antimicrobial activity.

This review focuses primarily on the importance of microbial endophytes as producers of natural compounds and the method of microbial biotransformation as a novel alternative to producing such compounds in industrially viable quantities.

Endophytes

Endophytes were first described by Heinrich Friedrich Link, a German botanist, in 1809. Originally known as “Entophytae,” they were defined as a distinct group of partially parasitic plant-living fungi. Bacon and White drafted the widely accepted definition of endophytes nearly 200 years later, in 2000, as “those microorganisms that are present in plant internal tissues and do not harm their host.” Endophytes can be used to develop technology that improves agricultural crop production, commercially important plants, and their valuable products as well as helping plants, adapt to harsh climatic changes by providing tolerance to various abiotic and biotic stresses [16, 17]. Endophytic microbes obtain plant nutrients and then release bioactive compounds and signaling molecules that can aid in root development, nutrient fixation, and the availability of nutrients in the rhizosphere that are absorbed by plants. Dreyfuss and Chapela [18] estimated that millions of endophytic fungi exist in the unique environment of 270,000–4,000,000 types of plant cells and intercellular space. Flavonoids, alkaloids, phenolic acids, glycosides, terpenoids, quinones, and other bioactive metabolites produced by endophytic fungi are beneficial to plants and humans. Fig. 1 depicts various potential biotechnological applications of microbial endophytes.

Fig. 1
figure 1

Potential application of microbial endophytes, Endophytic microorganisms play a critical role in the synthesis of bioactive metabolites, nanoparticles, and industrially significant enzymes, support plant growth, carry out biotransformation processes, and quicken phytoremediation or bioremediation processes

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The Relationship Between Host and Endophytes

Endophytic microbes spend the majority of their lives in the internal tissues of host plants. Plants provide a large and complex micro-habitat environment for endophytic organisms that live in the intercellular spaces of plant tissue [19]. The host–endophyte relationship can be mutualistic or antagonistic, depending on host specificity and host selectivity [20]. Endophytes may also be present in a metabolically hostile environment and can withstand host defense mechanisms at the same time [21]. It was discovered that closely related plant species can be inhabited by the same endophytes, while distinct endophytes can inhabit different tissues of the same plant, depending on the co-evolutionary genotypes of both plants and microorganisms, as well as other networks of interactions with environmental factors within the plant biome [19]. Plant–endophyte interactions are influenced by both the genotype of the participating species and the environmental conditions. Hameed et al. [22] found that the plant growth-promoting properties of rice endosphere-inhabiting endophytic bacteria were affected by a variety of factors, including host genotype, nutrient availability, and soil characteristics. Awareness about endophytic research is gradually revealing a better understanding of the complexities of various plant microbiome interactions. Endophytic microorganisms have been successfully used for the biological control of various plant diseases as well as to improve plant agronomic properties. They have been shown to increase yields and promote growth in potatoes, tomatoes, and rice, as well as to trigger resistance to both abiotic and biotic stress by producing antimicrobial compounds, competition for macronutrients, induced systemic resistance, and siderophores [23].

Endophytes’ promising biotechnological applications have fueled an increase in endophyte research. So far, the plant rhizosphere has produced the most beneficial microbes and their products that promote plant growth and/or health through direct and indirect ways. Endophytes can indirectly contribute to plant growth by suppressing plant diseases, degrading environmental pollutants, and reducing plant stresses. Endophytic microorganisms can also promote plant growth directly, for example, by production of hormones or by making nutrient available to plants [17]. Endophytes may also function as a versatile biological system that promotes growth by increasing host tolerance to environmental stress and producing highly valuable bioactive compounds for human well-being and health. Some endophytic microbes can also produce industrial enzymes and nanoparticles, which also have numerous applications in biotechnology.

Application of Endophytes in Plants Growth Promotion (PGP)

Most endophytic relationships promote plant growth. Endophytes stimulate plant growth through direct or indirect mechanisms, which are discussed in this section.

Direct Plant Growth Promotion

The colonization of endophytic microorganisms within the plant's internal tissues can result in increased agricultural yield via PGP mechanisms, as shown in Fig. 2. Healthy plants are more robust and less susceptible to disease. Microbes can promote plant health and vigor through a variety of mechanisms, including fixation of atmospheric nitrogen, production of siderophore to scavenge Fe+3 ions under Fe+3 conditions, solubilization of phosphorus and essential minerals, phytostimulation, biofertilization, stress tolerance induction, and rhizoremediation by protecting against environmental pollutants [9]. It has been observed that PGP traits are associated with multiple endophytes simultaneously [24]. Endophytic diazotrophic bacteria can provide nitrogen to plants via biological nitrogen fixation (BNF), which is an important nitrogen input in agriculture. Many crops benefit from BNF, which is aided by plant-promoting bacteria on the root surface and plant growth-promoting endophytic bacteria associated with internal tissue. Singh et al. [25] reported the isolation of diazotrophic endophytic bacteria (Pantoea cypripedii AF1 and Kosakonia arachidis EF1) from sugarcane roots and hypothesized that endophytic microorganisms could be associated with the biological fixation of large amounts of nitrogen.

Fig. 2
figure 2

The function of endophyte microbes in plant growth, Schematic representation of the main activities of plant growth-promoting endophytic microbes such as it can fix atmospheric nitrogen, solubilize phosphorus, iron uptake by synthesize siderophores compound, ACC deaminase activity lowering ethylene levels, production of antibiotics, and functional enzyme stimulating plant cell growth and development

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Endophytes regulate plant growth through the action of phytohormones and nutrient production via plant regulators which act as signaling molecules that affect various physiological processes of plant growth at very low concentrations [15]. Endosymbionts produce auxins, a phytohormone that promotes plant vegetative growth. Gibberellins in plants can induce elongation and cell division, while their exogenous application can improve plant growth in normal and stressed conditions, such as drought, salinity, and temperature [26]. Endophytic actinobacteria of the wheat crop, for example, Streptomyces olivaceoviridis, Streptomyces rimosus, and Streptomyces rochei, produced auxins, gibberellins, and cytokinin-like substances that positively influence plant growth [27].

The use of phosphate solubilizing microorganisms as inoculants improved plant phosphorus uptake, resulting in higher plant yields. A consortium of endophyte and rhizosphere phosphate solubilizing bacteria improved phosphorus use efficiency in wheat cultivars grown in phosphorus-deficient soils [28]. The phosphate solubilizing endophytic bacteria Enterobacter sp. J49 and Serratia sp. S119 isolated from peanut plants significantly promoted plant growth of soybean and maize on a microcosm scale, indicating that phosphate solubilizing bacteria could be used in various plant species to improve phosphate use efficiency [29]. Two endophytic fungi, which belong to genera of Penicillium and Aspergillus isolated from Taxus wallichiana roots, solubilized phosphate, from phosphate salts of calcium, aluminum, and iron by the production of phosphatase and phytase enzymes [30].

Endophytic bacteria have ability to produce siderophores, which are iron-chelating agents that can bind insoluble ferric ions. Plants can obtain iron from these bound siderophores through root-based chelate degradation or ligand exchange. Endophytic bacteria isolated from Cicer arietinum and Pisum sativum nodules and roots were tested for siderophore production [31]. Additionally, the dominant group of endophytic actinobacteria of New Zealand native medicinal plant Pseudowintera colorata belongs to genera Streptomyces and Nocardia and these organisms were found to solubilize phosphate and produce siderophores [32].

Endophytic fungi, such as P. chrysogenum (CAL1), Aspergillus sydowii (CAR12), and Aspergillus terreus (CAR14), isolated from Cymbidium aloifolium, a medicinal orchid plant, have been found to secrete bioactive antimicrobial siderophores [33]. The siderophore isolated from P. chrysogenum inhibited the virulent plant pathogens Ralstonia solanacearum, which causes bacterial wilt in groundnuts, and Xanthomonas oryzae pv. oryzae, which causes bacterial blight disease in rice, protecting both groundnuts and rice. Endophytic fungi, such as Paecilomyces formosus, Phoma glomerata, and Penicillium sp., aid in the growth of both genetically engineered and wild-type rice plants [34].

Indirect Plant Growth Promotion

Indirect mode of action of PGP includes the production of antibiotics, lytic enzymes, such as β-(1,3) glucanase and chitinase, production of aminocyclopropane-1-carboxylic acid (ACC) deaminase, antifungal molecules that cause lysis of fungal cell wall, and competition and inhibition of phytopathogens along with induction of systemic resistance. Plant growth can be indirectly promoted by reducing damage to plants infected with pathogenic bacteria or fungi. This is normally accomplished by pathogens being inhibited by plant growth-promoting rhizobacteria (PGPR). Plant diseases and insect pests seriously harm agricultural crop yield and cause significant drop in agricultural productivity. While chemical pesticides reduce the risk of pests and diseases, they also jeopardize the environment and human health [35].

Endophytic microorganisms have been extensively applied for the biological control of several plant diseases. Endophytic control of plant diseases has received a lot of attention in recent decades as a possible replacement for chemical agents in agriculture [24, 35]. Indigenous bacterial endophytes can be used as biological control agents against phytopathogens, which is an ecologically and environmentally sound approach to integrated plant disease management. Antagonist species can interfere with the development and survival of the pathogens. Rhizospheric bacteria have well-studied mechanisms for protecting plants against fungal phytopathogens. Endophytic bacteria are thought to use similar mechanisms to control fungal pathogens. Antibiosis and induced systemic resistance are well-studied biocontrol mechanisms for endophytic microbes. Endophytic Pseudomonas spp., for example, is one of the best examples of biocontrol agents because the bacteria provide resistance against various phytopathogens in different host plants. Pseudomonas fluorescens BRZ63, isolated from the internal tissues of the oilseed rape (Brassica napus L.), was found to be an excellent endophytic candidate for biocontrol of Rhizoctonia solani W70, Colletotrichum dematium K, Sclerotinia sclerotiorum K2291, and Fusarium avenaceum, according to Chlebek, et al. [36]. Pseudomonas putida was found as efficacious biocontrol agent against a wide range of pathogens, such as R. solani in potato [37]. An endophytic actinobacterial strain CEN26 of Centella asiatica was inhibitory against the fungal pathogen Alternaria brassicicola. It acted by inhibiting germination of conidia and morphological development [38].

Rice blast disease is a major factor influencing stable rice production in many rice growing countries around the globe. The disease is caused by the fungal pathogen Magnaporthe oryzae. Proteomic studies conducted during rice–M. oryzae interaction have led to the identification of several proteins eminently involved in pathogen perception, signal transduction, and the adjustment of metabolism to prevent plant disease [39]. Some of these proteins include receptor-like kinases, mitogen-activated protein kinases, and proteins related to reactive oxygen species (ROS) signaling and scavenging, hormone signaling, photosynthesis, secondary metabolism, protein degradation, and other defense responses.

PGPR showed hyperparasitic activity attack on pathogens through secretion of cell wall lytic enzymes, such as chitinases, proteases, glucanases, and cellulases [40]. Fusarium wilt is a common fungal disease that affects many plants, and controlling its infection is a major issue for farmers. Malfanova et al. [24]found that B. subtilis HC-8 isolated from the giant hogweed stem (Heracleum sosnowskyi) exhibited promising plant defense traits against wilt caused by the pathogenic fungi Fusarium solanum and Fusarium oxysporum sp. radicis-lycopersici (Forl), as well as Pythium ultimum. Cyclic lipopeptides produced by B. subtilis were responsible for disease suppression. Mousa et al. [41] isolated antifungal endophytes, such as Paenibacillus polymyxa and Citrobacter sp. from wild maize (teosinte), which produced antifungal compound fusaricidin and inhibited pathogen Fusarium graminearum. Endophytic bacteria associated with black pepper, such as Pseudomonas aeruginosa, P. putida, and Bacillus megaterium, have been reported as effective antagonists for biological control of phytophthora foot rot, with over 70% disease suppression in greenhouse trials [42].

Rabha et al. [43] demonstrated that the endophytic fungus Colletotrichum gloeosporioides showed strong antagonistic activity against tea pathogen Pestalotiopsis theae (64%) and moderate activity against Chryseobacterium camelliae (37%). Mejia et al. [44] isolated and screened endophytic fungi against three pathogens in cacao, Phytophthora palmivora, Moniliophthora perniciosa, and Moniliophthora roreri, and identified that antagonism was found in 27–65% of the endophytic isolates. The field trial results with the treatment of endophytic isolate C. gloeosporioides against M. roreri and P. palmivora revealed a significant reduction in damaged pod loss. Endophytic fungi were isolated from different oil palm sections and their antagonistic activity against Ganoderma boninense was demonstrated by using a dual culture assay [45]. The microscopic observations suggested that fungal endophytes attached themselves to G. boninense hyphae and caused abnormalities in hyphal morphology, such as hyphal swelling, distortion, and early branching to pathogens in the dual culture interaction zone, which may be due to the production of extracellular metabolites, such as chitinase in the medium. Only Trichoderma isolates, however, demonstrated high chitinase activity, indicating that they could be a powerful antagonist against G. boninense. More systematic studies on crop endophyte interactions are required to determine the full potential of endophytes in plant protection measures.

Furthermore, many endophytic bacteria boost plant growth by producing the enzyme ACC deaminase, which cleaves 1-aminocyclopropane-1-carboxylate (ACC), an immediate precursor of ethylene, to create ketobutyrate and ammonia. Plants that have been inoculated with PGPR generating ACC deaminase have longer roots and less inhibition of plant growth in response to environmental or pathogen-induced stress [46]. The presence of ACC deaminase activity has been investigated in various plant-isolated endophytic bacterial taxa, including Ralstonia, Azospirillum, Rhizobium, Enterobacter, Agrobacterium, Pseudomonas, Achromobacter, and Burkholderia [47].

Application of Endophytes in Bioremediation

Bioremediation is a method that utilizes living organisms to remove xenobiotics pollutants. Phytoremediation (mediated by endophytic microorganisms) and rhizoremediation are two bioremediation strategies that have been shown to be effective in removing harmful xenobiotic pollutants from the environment. Pollutant mobility, degradability, solubility, and bioavailability are all important factors in bioremediation [48]. This method has arisen for removing or sequestering metal particles, volatile organic compounds, crude oil elements, and radionuclides. The metabolic diversity of the microbial community promotes bioremediation, and the metabolic processes of endophytes make them essential tools for bioremediation. Endophytic microorganisms can play a significant role in the bioremediation of insecticides, pesticides, petrochemicals, herbicides, phenols/chlorophenols, and polychlorobiphenyls by promoting biotransformation, such as the conversion of chiral alcohols and propylene to epoxypropane [49]. The poplar endophyte P. putida was able to degrade the toxic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) from the soil after being inoculated into pea plants [50]. According to Verma et al. [51], the endophytic fungus Alternaria alternata (PCTS21) present in the leaves of Cupressus torulosa can degrade poly-aromatic hydrocarbons, such as phenanthrene, naphthalene, and anthracene, which are typical environmental pollutants with poisonous, genotoxic, mutagenic, and carcinogenic consequences. Data revealed that naphthalene degradation was the highest of all deemed hydrocarbons, at 36.8%. These findings suggest that the novel endophytic fungus A. alternata may be used in the bioremediation of these hazardous contaminants. Endophytic diversity has been studied for the degradation of even plastics, and two isolates of Pestalotiopsis microspora (E2712A and E3317B) have demonstrated the ability to efficiently degrade synthetic polymer polyester polyurethane in both liquid and solid suspensions [52]. Anaerobically grown P. microspora effectively degraded and used polyurethane as the sole carbon source, which was the first in recorded polyurethane biodegradation activities. The enzyme serine hydrolase formed by P. microspora has been shown by recombinant DNA technology to be capable of polyurethane degradation. Chanyal and Agrawal [53] isolated the laccase-producing endophytic fungus Daldinia sp. from C. torulosa and demonstrated textile dye decolorization. Laccase-based dye treatments provide a promising biotechnological method for removing dyes and aromatic compounds from industrial waste on a wide scale [5].

A team of researchers studied the Tobacco plant Nicotiana tabacum to investigate the function of endophytes in phytoremediation. Under Cadmium (Cd) stress, endophyte-inoculated N. tabacum produced more biomass, and inoculated plants had higher Cd concentrations than non-inoculated plants [54]. This means that endophytes can help with metal sequestration and toxicity reduction.

Plant–endophytes interactions can be used in the bioremediation of greenhouse gas emissions (particularly methane and carbon dioxide) to aid in the in situ alleviations of environmental pollutants without the need for extensive excavation of polluted soil [48]. There have been several experiments on vegetation-based greenhouse gas pollution. Endophytic methanotrophic bacteria from the genus Methylocella palustris and Methylocapsa acidiphila have been found in moss tissues of Sphagnum sp. These endophytic bacteria oxidize methane into carbon dioxide, which the host plant uses for photosynthesis (Fig. 3). As a result, methanotrophic endophytic bacteria will function as a natural methane filter with Sphagnum magellanicum reducing carbon dioxide and methane emissions from peatlands by up to 50% [55].

Fig. 3
figure 3

The role of endophytic methanotrophs in peat lands, Endophytic methanotrophic bacteria isolated from Sphagnum sp. act as a natural methane filter, recycling system carbon, and lowering CH4 and CO2 emissions from peat lands. In Fig. 3 red arrows denote the transport of methane from peat land to the atmosphere. The green circle represents endophytic methanotrophs in the endosphere of Sphagnum sp., whereas the dark red arrow represents methane oxidation to carbon dioxide by methanotrophs. The green and brown arrows represent CO2 fixation in plants via photosynthesis. CH4 oxidation is indicated by the blue arrow. Horizontal blue bar denotes water, whereas horizontal brown bar denotes pet land (Color figure online)

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Role of Endophytes in Bioactive Compounds Production

Endophytes are an outstanding source of varied natural resources due to their potential to inhabit a plethora of different biological microenvironments, i.e., plants growing under both atmospheric and harsh conditions. The isolation and screening of natural bioactive compounds for medicinal uses opened the way for the discovery of bioactive compounds. Endophytes produce bioactive compounds that help plants defend themselves against pathogens, and these compounds can lead to the discovery of new drugs [10]. Therefore, quite expectedly bioactive compounds produced by them found applications in both plant and human health sectors. Endophytic microorganisms from both Angiosperms and Gymnosperms have been widely analyzed to discover new secondary metabolites [4]. Endophytes have been isolated and characterized by numerous research groups from various plant components, with a list of such works provided in Table 1.

Table 1 Bioactive compounds produced by endophytes and their biological activity
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Endophytes derived from medicinal plants are a rich source of numerous functional metabolites [65]. Crude extracts of endophytes culture broth revealed many natural compounds, such as steroids, alkaloids, flavonoids, terpenoids, and glycosides, that are known to have antimicrobial [56], anticancer [66], antioxidant [62], antiviral, immunosuppressive [67], and antidiabetic functions. Thus, working into endophytes opens up new avenues for biotechnological applications.

Antimicrobial Activity

Natural products have long been used in traditional medicine and continue to contribute to low-cost disease control in developed countries. Endophytic fungi are likely to trigger a pathogenic attack resistance cycle by developing secondary metabolites of antimicrobial effects. The endophytic fungus Cryptosporiopsis cf. quercina was able to produce cryptocin in culture which has antifungal activity against Pyricularia oryzae, the causal agent of rice blast disease [56]. An endophytic fungus INFU/Hp/KF/34B recovered from the medicinal herb Hypericum perforatum (St. John’s Wort) produced hypericin, which has antimicrobial action against many pathogenic bacteria and fungi, including Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica, and Escherichia coli, and fungal species Aspergillus niger and Candida albicans [68]. Molecular analysis of the fungus based on a large subunit rRNA gene revealed 99% similarity to another fungal isolate, 9097 (accession number EF420068), that itself is a new unidentified fungus, similarly to other related taxa, for example, Chaetomium globosum (98%, accession number AY545729) and unidentified fungal isolate 9038 (98%, accession number EF420066). The endophytic fungus Periconia sp. was reported to produce piperine [5-(3, 4-methylenedioxyphenyl)-1-piperidinopent-2,4-dien-1-one] that displayed antibacterial activity against Mycobacterium tuberculosis and M. smegmatis [61]. Similarly, in China, fungal endophytes Chaetomium globosum and Penicillium minioluteum were isolated from the medicinal plant Litsea cubeba, and these endophytes demonstrated anti-pathogenic properties and may be a source of novel natural antimicrobial compounds [65]. The compound cytochalasin D were isolated from the endophytic fungus Xylaria sp., which was isolated from Bostrychia tenella. The compound presented antifungal activity [64]. Streptomyces sp. TQR12-4 isolated from Elite Citrus nobilis fruit showed antimicrobial activity and inhibited test pathogens Colletotrichum truncatum, Geotrichum candidum, F. oxysporum, and F. udum [69].

Antioxidant Activity

Many biological physiologic reactions produce ROS, such as superoxide anion (O2 −), hydroxyl radical (OH•), hydrogen peroxide (H2O2), and singlet oxygen (1O2), as byproducts that cause oxidative damage to biomolecules. ROS are also involved in the mechanism of programmed cell death and stress-response signaling. Since they are ubiquitous, both ROS and antioxidants are likely to play an important role in symbiotic interactions. Endophytic fungi help host plants respond to various abiotic and biotic stresses by generating antioxidants to interrupt the damaging chain reactions triggered by ROS [70].

Natural antioxidant compounds are widely found in fruits, vegetables, and medicinal plants and endophytes are likely to develop them in the host plant. Endophytic bacteria Staphylococcus epidermidis strain WDY6 associated with clove leaves (Syzygium aromaticum) produced the bioactive compound pyrazine which has antioxidant activity, with a 68.90% inhibition of 1,1-diphenyl-2-picrylhydrazy free radicals [71]. Furthermore, its remarkable antioxidant potential could be attributed to its higher content of alkaloid constituents, such as pyrazine, as well as their hydrogen donating ability, which makes them potent free radical scavengers. Endophytic Paenibacillus polymyxa isolated from the root tissue of Stemona japonica, a traditional Chinese medicine, produced exopolysaccharides that demonstrated strong scavenging activities on superoxide and hydroxyl radicals [72].

A large number of endophytic fungi with ROS scavenging activity were isolated from well-known Rhodiola plants with high antioxidant activity, implying that such plants and their associated endophytes may be potential sources of novel natural antioxidants. Endophytic fungi P. microspora associated with the plant Terminalia morobensis produced antioxidant metabolites, such as isopestacin and pestacin [62]. Endophytic fungi, specifically Penicillium citrinum CGJ-C2, were isolated from Tragia involucrata, and an ethyl acetate extract of P. citrinum CGJ-C2 demonstrated high antioxidant and cytotoxic activity [73].

Antiviral Activity

The emergence of new viruses and viral diseases, as well as the scarcity of vaccinations and antiviral medications, fuels the need for the discovery of new molecules [74]. Endophytic microbes have the ability to be a bioactive antiviral molecule reservoir. Endophytic bacillus species associated with cotton plants cause systemic resistance in the plant to pathogens [75]. This is most likely due to their secret antimicrobial peptides and fatty acids, which exhibit antiviral activity against Tobacco streak virus and promote cotton plant growth. An endophytic actinobacteria Streptomyces sp. strain isolated from the mangrove plant Bruguiera gymnorrhiza developed xiamycin, which had selective anti-HIV activity [76].

The endophytic cytonaema fungus produces cytotonic acids A and B, which inhibit the human cytomegalovirus (hCMV) protease. Metabolites obtained from desert plant endophytic fungi have the potential to be used to identify potent HIV-1 replication inhibitors [77]. A crude extract of the endophyte fungus Pleospora tarda isolated from the medicinal plant Ephedra aphylla was recently confirmed to have antiviral efficacy, as it blocked the replication of Vesicular stomatitis virus and Herpes simplex virus-2 viruses. P. tarda demonstrated antiviral activity through the bioactive compounds alternariol and alternariol-(9)-methyl ether [78].

Anticancer Activity

Cancer has been a leading cause of death worldwide. The rising number of cancer deaths necessitates the development of new anticancer drugs. Advances in cancer therapy are incorporating the manufacture of biologically derived novel and improved chemotherapeutic drugs with distinct bioactivities. Endophytic fungi are a rich source of bioactive metabolites that have the potential to be novel bioactive chemotherapy compounds [66]. Novel compounds developed by some endophytic fungi are useful in anticancer assays in vitro. Taxol is the world's first billion-dollar plant-derived anticancer drug to be used successfully in the treatment of various types of human cancer. Gliocladium sp., a novel taxol synthesizing fungus, was isolated and characterized from Taxus baccata [59]. Mucor fragilis, an endophytic fungus, may develop anticancer bioactive metabolites, including kaempferol and podophyllotoxin [60]. Guanacastane di-terpenoids obtained from the plant endophytic fungus Cercospora sp. demonstrated anticancer efficacy [79]. Endophytic microbes isolated from Miquelia dentata (Icacinaceae) were able to produce bioactive metabolites, such as camptothecin (CPT) and a CPT variant, 9-methoxy CPT (9-MeO-CPT), which demonstrated anticancer activity [57].

The cytotoxic activity of (9Z)-octadecenoic acid methyl ester and (9Z,12Z)-octadecadienoic acid methyl ester isolated from the fungal endophyte F. oxysporum SS46 isolated from the medicinal plant Smallanthus sonchifolius was reported by Nascimento et al. [80]. The crude extracts were more active against cancerous cells at concentrations ranging from 125 to 500 µg mL−1. Fungal secondary metabolites at a concentration of 10 µg mL−1 showed such desirable effects on the cell viability of HEK cells [4].

Crude extracts of the bacterial endophyte Acinetobacter guillouiae isolated from Crinum macowanii bulbs demonstrated anticancer activity against U87MG glioblastoma cell lines [81]. One novel ansamycin, namely, naphthomycin K, together with two known naphthomycins A and E, were isolated from the endophytic actinomycete strain Streptomyces sp. CS of the medicinal plant Maytenus hookeri [63]. Naphthomycin K showed evident cytotoxicity against P388 and A-549 cell lines, but no inhibitory activities against Staphylococcus aureus and Mycobacterium tuberculosis.

Immunosuppressive Activity

To prevent allograft rejection in transplant recipients, a wide range of immunosuppressive drugs is required. They may be used to treat autoimmune diseases, like rheumatoid arthritis and insulin-dependent diabetes. Immunosuppressive drug delivery appears to have become a routine therapeutic procedure to prevent the complications involved with allograft transplantation. Immunosuppressive drugs, such as cyclosporine A, sirolimus, and others, have significant adverse effects, including kidney and nervous system toxicity, as well as the risk of pneumonia, asthma, hyperlipidemia, new development of post-transplant diabetes mellitus, and cancer. Endophytes can play an important role in the development of effective and safe immunosuppressants. The endophytic fungus Fusarium subglutinans isolated from Tripterygium wilfordii produces immunosuppressive but non-cytotoxic di-terpene pyrone subglutinol A [58]. A novel effective immunosuppressant (−) mycousnine enamine, a novel dibenzofurane derivative of (-) mycousnine from endophytic fungus Mycosphaerella nawae was found to have low toxicity, high and selective immunosuppressive activity that selectively inhibits T cell proliferation, suppresses the expression of surface activation antigens CD25 and CD69 and formation and expression of cytokines interleukin-2, as well as interferon γ in activated T cells [67]. Three compounds isolated from Pestalotiopsis leucoth, an endophytic fungus from T. wilfordii, were found to be effective on T and B cells as well as monocytes. These in vitro potentials of fungal compounds should be investigated as alternatives to current immunosuppressive drugs due to their profound immunomodulatory effects and low cytotoxicity [82].

Biological Synthesis of Nanoparticles

Nanotechnology is defined as the technological process of designing, characterization, manufacturing, and application of nanometer-scale devices, structures, and systems. Nanobiotechnology has arisen in recent years as an interface of biotechnology and nanotechnology to establish simple, green, biosynthetic, and eco-friendly technology for the development of nanoparticles of varying sizes, shapes, chemical composition, and regulated dispersity due to their beneficial uses for human welfare [83]. Nanoparticles are small versions of conventional materials that are used in traditional methods to have resource efficiency and environmental advantages, such as emission control, heat and UV resistance, and so on. Nanoparticles may be prepared using a number of methods from a wide range of materials. Physical and chemical methods are less preferred over biological systems due to the prevalence of toxic chemicals [84]. The biogenic productions of nanoparticles are far superior, in several ways, to those particles produced by chemical methods. Despite that the latter methods can produce large quantities of nanoparticles with a defined size and shape in a relatively short time, they are complicated, outdated, costly, and inefficient and produce hazardous toxic wastes that are harmful, not only to the environment but also to human health. With an enzymatic process, the use of expensive chemicals is eliminated, and the more acceptable “green” route is not as energy intensive as the chemical method and is also environment friendly. Nanoparticles have promising applications in therapeutics, medicine, environmental treatment, computing, and agriculture, among others [85].

Silver nanoparticles are beneficial in biotechnological applications, such as biomedical testing and bioremediation in keeping human life easy and healthy. Silver nanoparticles are synthesized using physical, chemical, and biological methods in which both physical and chemical methods involve unwanted chemicals that generate hazardous byproducts [86]. The use of biological systems, such as microbes, plants, and enzymes, to synthesize numerous silver nanoparticles of varying sizes and shapes with possible applications as efficient antimicrobial agents has emerged as a novel research area. Production of nanoparticles using biological methods that are of immense importance in medicine and nanotechnology has been documented for various microorganisms. The process of silver nanoparticle synthesis using endophytic fungi includes subsequent steps: capturing of Silver (Ag+) ions at the surface and their subsequent reduction by the enzymes located on the cell surface of the fungal system.

The biosynthesis of silver nanoparticles using endophytes fungi has been documented as a “green” solution to the chemical methodology. Saccharomonospora sp., an endophytic actinomycete isolated from A. indica root tissues synthesized gold nanoparticles of varying sizes [87]. Sunkar and Nachiyar [88] reported that B. cereus isolated from Garcinia xanthochymus synthesized silver nanoparticles ranging in size from 11 to 16 nm. Table 2 displays a list of endophytes capable of producing various nanoparticles.

Table 2 Synthesis of various nanoparticles by endophytic microorganisms
Full size table

Scientists and pharmaceutical firms have been encouraged to search for new antibacterial agents as a result of the outbreaks of infectious diseases spread by pathogens and an unexpected increase in antibiotic resistance. Nanomaterials have emerged as promising antimicrobial agents due to their distinct chemical, biological, and physical properties, as well as their high surface area-to-volume ratio. Silver has been used as a defensive inorganic antimicrobial agent against nearly 650 different types of disease-causing microorganisms [85]. It is an effective antibiotic-resistant bacteria antagonist and has other biological applications, such as anti-inflammatory action, wound healing, and infection prevention. Ag+ ions and their compounds are extremely toxic to microorganisms, with a strong cidal effect on certain species of bacteria, but are relatively non-toxic to animal cells. Ag+ ions are used in the preparation of resin-based dental composites, medical device coatings, bone cement, and ion exchange fibers due to their excellent properties. Furthermore, silver nanoparticles (AgNPs) exhibit more effective bioactivity than other salts due to their extremely high surface area [90].

AgNPs’ antimicrobial properties led to their use in the military, medication, agriculture, cosmetics and accessories, packaging, and other industries. Biological synthesis of AgNP’s at laboratory scale is quite inexpensive and non-toxic, eco-friendly as compared to the chemical methods. AgNPs synthesized from the fungal endophyte Pestalotiopsis versicolor were tested for antimicrobial activity against three pathogens: B. subtilis, P. aeruginosa, and S. enterica, and the results revealed that AgNPs have promising medicinal activity against all of the pathogens tested [6]. The crude extract of endophytic fungus P. versicolor was used to produce novel, feasible and safe AgNPs without utilizing any conventional reducing and capping agents. These AgNPs demonstrated significant antimicrobial activity toward human pathogens as well as azo dye-degrading capacity for Rhodamine B, Congo red, and Orange G [6]. The AgNPs bind to the bacterial cell membrane and permeate it. Nanoparticles bind to sulfur-containing proteins and phosphorus-containing DNA inside bacteria, altering their structural and functional properties and inhibiting cell division, the respiratory chain of microbes, and, eventually, cell death [91].

Application in Enzyme Production

Endophytes are believed to release enzymes that can directly inhibit the activities of plant pathogens and can degrade fungal cell walls [40]. Endophytic fungi play an important role in the production of various hydrolytic enzymes that act on plant-derived macromolecules. The market for new sources of enzymes with improved thermal stability and pH profiles is growing in a variety of industries [92]. This demand has urged the use of endophytes as enzyme sources in promising industrial applications in the biotechnology, agricultural, and pharmaceutical industries [53]. Enzymes derived from fungal endophytes are widely used to facilitate the processing of almost all raw materials in the food and beverages, confectionery, textiles, pulp and paper, and leather industries. They are more stable than enzymes derived from other sources, particularly bacterial enzymes. Endophytic fungi can also produce enzymes that aid in the degradation of the complex structure of recalcitrant lignocelluloses, making them more efficient in the production of biofuel ethanol and other value-added chemicals from lignocellulosic biomass [93].

Fungal endophytes are emerging as a novel reservoir of industrially useful enzymes, such as laccases, lipases, amylases, and proteases. Laccase is present in both Ascomycota and Basidiomycota and it is particularly abundant in many white-rot fungi and has an excellent potency to degrade lignin. Laccases can degrade both phenolic and non-phenolic compounds. Laccase’s ability to detoxify a wide range of pollutants makes it suitable for use in a variety of industries, including paper, pulp, petrochemical, and textile [5]. Acremonium zeae, a maize-derived endophyte, exhibited extracellular hydrolytic enzyme degrading hemicellulose, which was useful in bio-converting lignocellulosic biomass into fermentable sugars [94]. Bhardwaz et al. [92] isolated an amylolytic endophytic fungus Penicillium frequentans from Pinus roxburghii. In addition, the amylase production of P. frequentans was investigated under a variety of pH, temperature, carbon, and nitrogen sources. The maximal amylase productivity was achieved on incubation at pH 7 and 30 °C. Fungal endophytes isolated from six medicinal plants in the Western Ghats of Karnataka, India, revealed that 40% were positive for asparaginase, 29% for amylase, 28% for cellulase, and 18% for pectinase [95]. Laccase-producing Daldinia sp. was effective in decolorizing synthetic dyes and turned out to be promising in bioremediation of colored wastewater of textile, food, and aquaculture industries [53].

Role of Endophytes in Biotransformation

Biotransformation is a process of using biological systems to carry out chemical conversions of their non-natural substrates [96]. The process can be conducted under mild reaction conditions as compared to a chemical synthesis environment without the need for high energy consumption and can reduce undesired byproducts and costs. As a result, it is an efficient method of producing novel compounds while overcoming the drawbacks associated with chemical synthesis processes. Biotransformation increases the productivity of the desired compound in an environmentally safe manner. Biotransformation uses microbial cultures or their metabolic enzymatic systems for the conversion of steroids lipids, lignans, di-terpenes, tri-terpenes, mono-terpenes, alkaloids, and a few synthetic chemicals, which carry out stereoselective and stereospecific processes for the generation of new bioactive molecules [96]. To colonize plant tissues and to use their nutrients, endophytic microorganisms produce the required enzymes that help in their survival within the host plant [1]. Therefore, in the chemical transformation of natural products/drugs of interest, endophytes can be used as biocatalysts. Biotransformation methods have numerous applications in the pharmaceutical and food industries, particularly in the production of bioactive compounds, such as antimicrobials, flavoring agents (vanillin, essential oils), antioxidants (eugenol), alkaloids, antifungal and antiviral agents, and anti-inflammatory agents (cineole) [14].

Endophytes are known to be used in the biotransformation of terpenes to produce new compounds. Terpenes are a large and diverse class of naturally occurring compounds that have fascinated the interest of industry due to their use in the flavor and fragrance industries. Terpene biotransformation has been widely used to generate volatile organic compounds, which are involved in the development of pure flavors and fragrances under mild reaction conditions [97]. Bier et al. [98] investigated limonene biotransformation using a fungal endophyte Phomopsis sp. extracted from Pinus taeda, and the studied strain exhibited divergent metabolic behavior, producing carvone, terpineol, and limonene-1, 2-diol under different conditions. The ability to biotransform natural products, such as curcumin pigment [99], betulinic and betulonic acids [100], alkaloids, and taxoids have been studied in some endophytic microbes.

Conclusion

Endophytes have unquestionably proven to be very beneficial, having a positive impact on plants, the environment, and humans in a variety of ways. Endophytic microorganisms, for example, can synthesize bioactive metabolites and industrially important enzymes, promote plant growth, carry out biotransformation processes, and accelerate phytoremediation or bioremediation processes. To efficiently deliver these endophytic capabilities, an integrated approach to studying endophytic systems and determining the most advantageous interaction between plants and microorganisms is required. The endophyte–plant interaction should be extensively investigated in terms of survival instinct and endophyte response to their surrounding environment, which can contribute to a better understanding of which plants to explore and study for valuable endophytic microfloral components. Innovative biotechnological tools, such as molecular studies, may contribute to a better understanding of endophyte ecology, metabolic abilities, and plant–endophyte interactions. A deep understanding of this research field may aid in product development and have economic and environmental implications.