Endophytic bacteria: a new source of bioactive compounds

Abstract

In recent years, bioactive compounds are in high demand in the pharmaceuticals and naturopathy, due to their health benefits to human and plants. Microorganisms synthesize these compounds and some enzymes either alone or in association with plants. Microbes residing inside the plant tissues, known as endophytes, also produce an array of these compounds. Endophytic actinomycetes act as a promising resource of biotechnologically valuable bioactive compounds and secondary metabolites. Endophytic Streptomyces sp. produced some novel antibiotics which are effective against multi-drug-resistant bacteria Antimicrobial agents produced by endophytes are eco-friendly, toxic to pathogens and do not harm the human. Endophytic inoculation of the plants modulates the synthesis of bioactive compounds with high pharmaceutical properties besides promoting growth of the plants. Hydrolases, the extracellular enzymes, produced by endophytic bacteria, help the plants to establish systemic resistance against pathogens invasion. Phytohormones produced by endophytes play an essential role in plant development and drought resistance management. The high diversity of endophytes and their adaptation to various environmental stresses seem to be an untapped source of new secondary metabolites. The present review summarizes the role of endophytic bacteria in synthesis and modulation of bioactive compounds.

Introduction

The “bioactive” or “biologically active” compounds are extra-nutritional constituents present in small quantities in lipid-rich foods and plant products (Cammack et al. 2006). These compounds are mostly produced by plants and microbes, and have broad pharmaceutical properties including anti-cancer, cardiovascular, anti-lipidemic, anti-hypertensive, anti-glycaemic, antithrombotic, anti-atherogenic and anti-diabetic (Puri et al. 2005; Chang et al. 2013; Atanasov et al. 2015; Villaescusa et al. 2015). Nowadays, bioactive compounds are used as preferred synthetic medicines for various diseases with very few side effects (Chang et al. 2013).

The endophytic fungi, bacteria and actinomycetes play a significant role in the production of bioactive compounds. Bioactive compounds like alkaloids, steroids, terpenoids, peptides, polyketones, flavonoids, quinols and phenols, and the natural insecticide azadirachtin produced by endophytic bacteria (Li et al. 2008; Kusari et al. 2012; Molina et al. 2012) have agricultural, industrial and medical applications (Hallmann et al. 1997; Kobayashi and Palumbo 2000; Zinniel et al. 2002).

Endophytic microbes spend most of their life cycle within the plant tissues without causing any visible damage to the host plant. Many endophytes also secrete specialized metabolites or biologically active compounds (Liarzi et al. 2016). Endophytic bacteria are also having the potential due to their ability to produce plant growth hormones, phosphate solubilization, nutrient acquisition and fixation of N₂ (Glick 2012).

Synthesis of bioactive compounds by endophytic microbes

The bioactive compounds synthesized by endophytes that help the host plant to develop systemic resistance against pathogens are also used in the pharmaceutical industries as antibiotics, anti-cancer, anti-viral, anti-diabetic and other bioactive compounds (Guo et al. 2008).

Endophytic fungi

Endophytic fungi are one of the major potential sources for the production of valuable bioactive compounds (Dreyfuss and Chapela 1994). Pestalotiopsis neglecta BAB-5510, an endophytic fungus of Cupressus torulosa, is considered to be a promising source of phenols, flavonoids, terpenoids, alkaloids, tannins, carbohydrates and saponin (Sharma et al. 2016), while Gilmaniella sp. AL12, an endophytic fungus, can stimulate Atractylodes lancea to produce volatile oils such as β-caryophyllene, zingiberene, caryophyllene oxide, β-sesquiphellandrene, hinesol, β-eudesmol and atractylone (Chen et al. 2016). Among the bioactive compounds, the antioxidants are the major compounds, frequently in discussions for good health and preventing diseases (Perucka and Materska 2003; Sanatombi and Sharma 2008; Al Othman et al. 2011). Capsaicin, a bioactive compound, abundantly found in red and chili peppers has been used as a medicine to remedy pain and as anti-cancerous agent for various human cancers. Alternaria alternata, an endophytic fungus isolated from Capsicum annum, produces capsaicin (Devari et al. 2014; Clark and Lee 2016). The endophytic organisms also produced various enzymes having pharmaceutical potential. Eurotium sp. an endophytic fungus, isolated from rhizomes of Curcuma longa produced asparaginase, an important anti-cancer enzyme (Jalgaonwala and Mahajan 2014). Endophytic fungus Huperzia serrata strains, L10Q37 and LQ2F02, also showed anti-acetylcholinesterase activity (Zhejian et al. 2015). Talaromyces pinophilus, an endophytic fungus isolated from strawberry tree (Arbutus unedo), produced siderophore ferrirubin, platelet-aggregation inhibitor herquline B and the antibiotic 3-O-methylfunicone. This strain also exhibited toxic effects against the pea aphid Acyrthosiphon pisum (Homoptera aphidiidae) (Vinale et al. 2017). The endophytic fungus Fusarium oxysporum 162 produced nematode antagonistic compounds, 4-hydroxybenzoic acid, indole-3-acetic acid (IAA) and gibepyrone D (Liu et al. 2016; Bogner et al. 2017).

Endophytic actinomycetes

Endophytic actinomycetes appear to be the promising source of bioactive agents, which can also be exploited for protection of crops and production of therapeutic agents (Balagurunathan and Radhakrishnan 2010; Prashith-Kekuda 2016). To date, more than 140 actinomycetes genera have been described and only a few of them produced majority of the known essential antibiotics (Jensen et al. 2005; Bull and Stach 2007; Pimentel-Elardo et al. 2010). Actinomycetes produce different types of secondary metabolites; many of these possess biological activities and have the potential to develop as therapeutic agents. Marine actinomycetes are underexploited source of novel secondary metabolites (Lam 2006). Streptomyces rochei CH1, an endophytic actinomycete of Cinnamomum sp., showed significant antibacterial activity against various test pathogens like Aeromonas caviae, Vibrio parahemolyticus and Pseudomonas aeruginosa (Roy and Banerjee 2015). Streptomyces cyaneofuscatus (KY287599) showed broad spectrum antimicrobial activities against Escherichia coli MTCC 739, P. aeruginosa MTCC 2453, Micrococcus luteus NCIM 2170, Staphylococcus aureus MTCC and yeast pathogen Candida albicans MTCC 3017. Streptomyces KX852460 also showed anti-fungal activity against Rhizoctonia solani AG-3 KX852461, the causative agent of target spot disease of tobacco leaf (Ahsan et al. 2017; Zothanpuia et al. 2017).

Endophytic bacteria

Majority of the endophytic bacteria showed beneficial effects like enhancement of biological N₂-fixation, production of phytohormones, solubilization of phosphate and inhibition of ethylene (C₂H₂) biosynthesis in response to biotic and abiotic stresses and have bio-control activity. More than 300 endophytic actinobacteria and bacteria belonging to the genera Streptomyces, Nocardiopsis, Brevibacterium, Microbacterium, Tsukamurella, Arthrobacter, Brachybacterium, Nocardia, Rhodococcus, Kocuria, Nocardioides, and Pseudonocardia were isolated from different tissues of Dracaena cochinchinensis Lour. (a traditional Chinese medicine known as dragon’s blood). Of these, 17 strains having antimicrobial and anthracyclines-producing activities also showed anti-fungal and cytotoxic activities against two human cancer cell lines, MCF-7 and Hep G2 (Dudeja and Giri 2014; Salam et al. 2017).

Mode of entry and establishment of endophytic bacteria in the plant

Endophytic bacteria were found in various environments which include tropic, temperate, aquatic, xerophytic, deserts, Antarctic, geothermal soils, rainforests, mangrove swamps and also coastal forests (Strobel et al. 2002; Suryanarayanan and Murali 2006). Endophyte–plant interaction is controlled by the genes of both organisms and modulated by the environmental conditions (Battistoni et al. 2005; Rosenblueth and Romero 2006). Obligate bacterial endophytes are strictly dependent on their host plant for their growth while facultative endophytes are biphasic alternating between plants and the soil.

Endophytes are transmitted through the seeds or recruited from the soil rhizosphere. They enter the host plant through the cracks formed in the lateral root junction or wound caused by microbial or nematodes phytopathogens (Chi et al. 2005) and quickly spread to the endorhizosphere. Entry of endophytic bacteria in the plant roots also occurs through root hairs and spaces between epidermal cells (Hardoim et al. 2008). In the invasive process, the degradation of plant cell envelop occurs by enzymatic activity, such as production of endoglucanases, pectinases and cellulases which assist them to colonize endorhizosphere. Endoglucanases loosen larger cellulose fiber and may help in entry to the plant. In addition, exoglucanases may also help in the colonization process (Reinhold-Hurek and Hurek 2011). Some strains of Streptomyces have been reported to produce hydrolytic cell wall-degrading enzymes such as chitinases, cellulases, hemicellulases, amylases and glucanases along with lignin-degrading enzymes. Endophytic Streptosporangium sp. from maize produced glucoamylase. The cell wall degrading enzymes, endogluconase and polygalacturonase, seem to be required for the infection of Vitis vinifera by Burkholderia sp. (Compant et al. 2005) (Fig. 1).

Fig. 1.

Routes of entry of endophytic bacteria

Bioactive compounds synthesized by endophytic bacteria

Bacterial endophytes have several potential applications in pharmaceutical and drug discovery (Strobel 2006; Guo et al. 2008). Endophytes associated with ethnomedicinal plants serve as a potential source of natural products for application in oxidative stress and as new bioactive agents (Nongkhlaw and Joshi 2015). The antimicrobial agents counteract the multi-drug resistance (MDR) in pathogenic microbes. Many microorganisms of agricultural concern have also acquired resistance to the commonly used antimicrobial compounds and the interest in natural methods of pathogen control through new, eco-friendly agents has been increasing day by day. Amines and amides are the common metabolites from endophytes that are toxic to insects but not mammals. Endophytes also produce extracellular hydrolyases such as cellulases, proteinase, lipases and esterases to establish resistance against plant invasions (Tan and Zou 2001). Endophytic bacteria associated with Hypericum perforatum and Ziziphora capitata belong to Arthrobacter, Achromobacter, Bacillus, Enterobacter, Erwinia, Pseudomonas, Pantoea, Serratia, and Stenotrophomonas. H. perforatum with antibacterial activity supported colonization of more bacteria with antagonistic activity, as compared to Z. capitata. Theses isolates were able to control tomato root rot caused by F. oxysporum (Egamberdieva et al. 2017) (Fig. 2).

Fig. 2.

Bioactive compounds synthesized by endophytic bacteria

Secondary metabolites

Secondary metabolites, though not essential for growth of an organism, play an adaptive role in functioning as the defense compound or the signaling molecule during ecological interactions and environmental stresses. Endophytic microorganisms produce low-molecular weight secondary metabolites that include antimicrobial compounds, phytohormones, or their precursors, vitamins like B12 (Ivanova et al. 2006) and B1 (Mercado and Bakker 2007), bioprotectants (Trotsenko and Khmelenina 2002). Several secondary metabolites are alkaloids, steroids, terpenoids, peptides, polyketones, flavonoids, quinols and phenols. These compounds also have important role in therapeutic applications such as anti-cancer, antioxidant, antimicrobial, anti-inflammatory, and immunosuppressive agents (Korkina 2007).

Secondary metabolites synthesis

Some endophytic bacteria modulate the production of secondary metabolites. Microbial secondary metabolites are synthesized from only a few precursors of primary metabolism with a relatively small number (Demain and Fang 2000). Endophytes synthesize secondary metabolites via a variety of pathways, e.g., polyketide, isoprenoid or amino acid derivation (Jalgaonwala 2013). However, the biosynthetic pathways are responsible for the production of both primary and secondary metabolites (Nicolaou et al. 2011) (Fig. 3).

Fig. 3.

Pathways for the synthesis of some secondary metabolites

The high species diversity of endophytes and their adaption to various environments could be considered a rich and almost un-trapped source of new secondary metabolites for pharmaceutical or agricultural applications (Bacon and White 2000). Nature has provided a broad spectrum of structurally diverse secondary metabolites (Verpoorte 1998; Maier et al. 1999). These metabolites act as biofilm, toxins, virulence factors (Raaijmakers and Mazzola 2012) and interfering agents with the hormone signaling in plants (Lopez et al. 2008; Glick 2012). The production and modulation of auxins and C₂H₂ by endophytic bacteria–plant interactions play an essential role in plant development and drought stress management (Hardoim et al. 2008; Glick 2012).

Terpenoids

Terpenes are derived biosynthetically from isoprene units. Approximately, 50,000 terpenoid metabolites including monoterpenes, sesquiterpenes, and di-terpenes representing nearly 400 distinct structural families have been isolated from plants, fungi and bacteria. In contrast, a relatively minor fraction of these widely occurring metabolites has been identified in prokaryotes (Yamada et al. 2015). Among the numerous volatiles, the most common Streptomyces terpenoids, geosmin, 2-methylisoborneol, tricyclic α, β-unsaturated ketone and albaflavenone are the well-known volatile odoriferous microbial metabolites. The sesquiterpenoid antibiotic, pentalenolactone is the common metabolite isolated from more than 30 species of Streptomyces (Takahashi et al. 1983). Streptomyces exfoliatus UC5319 produced pentalenene synthase (ADO85594); the first characterized, cloned, and sequenced terpene synthase from Streptomyces (Lesburg et al. 1997). The endophytic bacterium Pseudomonas fluorescens ALEB7B can switch on the generation of reactive oxygen species (ROS) in A. lancea (a Chinese medicinal plant that contains oxygenous sesquiterpenoids) that leads to increased oxygenous sesquiterpenoid content (Zhou et al. 2015).

Alkaloids

Alkaloids, the low-molecular-weight, nitrogen-containing compounds, are important in pharmaceutical industries because of their high biological activities. Most alkaloids are derived from amines produced by the decarboxylation of amino acids, such as histidine, lysine, ornithine, tryptophan and tyrosine. Endophytes produce alkaloids as the secondary metabolites that have diverse biological potential as anti-fungal, anti-cancer, and anti-viral agents (Silva et al. 2007). Endophytic Bacillus cereus, Aranicola proteolyticus, Serratia liquefaciens, Bacillus thuringiensis, and Bacillus licheniformis isolated from Pinellia ternata have the ability to produce alkaloids (guanosine and inosine) in fermentation broth similar to their host plant (Liu et al. 2015). The capsular endophyte Acinetobacter SB1B in Opium poppy unregulated the expression of key genes for the benzylisoquinoline alkaloid (BIA) biosynthesis except thebaine and codeine. In contrast, Marmoricola sp. SM3B, another endophyte, could up-regulate the biosynthesis of both thebaine and codeine. Acinetobactor and Marmoricola sp. as microbial inoculants modulated the alkaloid producing genes in Opium poppy (Pandey et al. 2016).

Phenols

Among the different dietary bioactive compounds, polyphenols constitute an interesting group as some possess important biological activities including antioxidant, anti-carcinogenic or antimicrobial activities. They have been reported to lower the risks of many chronic diseases, including cancer, cardiovascular diseases, chronic inflammation, and many degenerative diseases. Phenolic compounds may be synthesized by the shikimate pathway (Kyselova 2011; Valdes et al. 2015; Carvalho et al. 2016; Lai Thi Ngoc Ha 2016). Dietary polyphenols may contribute to the maintenance of intestinal health by preserving the gut microbial balance through stimulation of the growth of beneficial bacteria (i.e., lactobacilli and bifidobacteria) and inhibition of pathogenic bacteria, exerting probiotic like effect (Duenas et al. 2015).

Endophytic bacterial isolates P. fluorescens Endo2 and Endo35 on inoculation induced systemic resistance against dry root rot of black gram (Vigna mungo L.) caused by Macrophomina phaseolina under glasshouse conditions. The bacterized black gram plants inoculated with dry root rot pathogen showed increased activities of peroxidase (PO), polyphenol oxidase (PPO), phenylalanine ammonia lyase (PAL) in addition to accumulation of phenolics and lignin (Karthikeyan et al. 2005). Inoculation of Talh tree (Acacia gerrardii Benth.) with endophytic bacterium B. subtilis (BERA 71) in combination with arbuscular mycorrhizal fungi (AMF) (Rhizophagus intraradices; Claroideoglomus etunicatum and Funneliformis mosseae) not only induced the acquired systemic resistance in plant but turned out to be potentially beneficial in ameliorating the deleterious impact of salinity on plant metabolism by modulating the osmoregulatory system (glycine, betaine, proline and phenols) and antioxidant enzymes system (Hashem et al. 2016).

Phytohormones and defense enzymes

Phytohormones are signal molecules that coordinate cellular activities and control plant growth and development. They play crucial roles in regulating plant responses to various stresses at extremely low concentrations. Bacterial endophytes and plants interactions result in the production and modulation of plant hormones (Lopez et al. 2008; Glick 2012). IAA is the most common, naturally occurring, plant hormone of the auxins class. The endophytic B. cereus (ECL1), B. thuringiensis (ECL2), Bacillus sp. (ECL3), Bacillus pumilis (ECL4), Pseudomonas putida (ECL5), and Clavibacter michiganensis (ECL6) isolated from C. longa L. produced IAA (Javid et al. 2011; Kumar et al. 2016). Pseudomonas, Agrobacterium and Bacillus isolated from the root of Cassia tora produced phytohormones and solubilized tricalcium phosphate (Kumar et al. 2015). Endophytic Artherobacter EZB-4 and Bacillus EZB-8 isolated from the pepper plant (Capsicum annum L.) produced IAA and increased the plant biomass. These endophytic bacteria also caused a significant reduction in up or down-regulation of the stress inducible genes (CaACCO and CaLTPI) compared to the gene expression in non-inoculated plants. Both the strains reduced osmotic and drought stresses (Sziderics et al. 2007). Achromobacter piechaudi E6S facilitated the plant growth by producting IAA, 1-aminocyclopropane-1-carboxylate (ACC) deaminase and solubilizing phosphate (Ma et al. 2016).

Abscisic acid (ABA) is considered as a plant stress hormone and is responsible for many kinds of stresses including water, salt, and cold temperatures. Drought is one of the stresses limiting crop production throughout the world. It is the single most devastating environmental constraint which hampers crop productivity more than any other stress (Farooq et al. 2012; Lambers et al. 2008). ABA and gibberellins (GA) produced by endophyte Azospirillum lipoferum alleviated the drought stress in maize (Cohen et al. 2009). Endophytic B. amyloliquefaciens SB-9 isolated from grapewine secreted high level of melatonin and produced three intermediates of melatonin biosynthetic pathway namely 5-hydroxytryptophan, serotonin and N-acetylserotonin. Serratia marcescens UPM39B3, an endophytic strain, induced the production of peroxidase, polyphenol oxidase, phenylalanine and ammonia lyase, besides total soluble phenols and lignothioglycolic acid in banana plantlets. Colonization of B. amyloliquefaciens SB-9 was also able to counteract the adverse effect of salt and drought-induced stresses by reducing the production of malondialdehyde (MDA) and reactive oxygen species (ROS) in grapewine roots (Jiao et al. 2016).

Besides phytohormones, salicylic acid (SA) is a critical plant hormone involved in various processes, such as seed germination, root initiation, stomatal closure, floral induction, and thermogenesis, besides the tolerance of plant to biotic and abiotic stresses. Endophytic bacteria enhanced the growth of sunflower seedlings under water stress, through the production of SA which also inhibited the growth of pathogenic fungi (Forchetti et al. 2010; Klessig et al. 2016).

Endophytic bacteria induced modulation of secondary metabolites production

Endophytic bacteria can be applied using different delivery techniques depending on need and growth stages of the plant. The seed treatment and foliar spray with bacterial endophytes seem to be economical because of lower cost. However, our knowledge of how bacterial endophytes enter and colonize plants is limited. Some endophytic plant growth promoting bacteria (PGPB) used as microbial inoculants enhanced the synthesis of biologically active compounds in the host plant. Turmeric rhizome contains a number of phenolic compounds, curcuminoids and sesquiterpenoids. Inoculation of turmeric rhizomes with endophytic Azotobactor chroococcum CL13 enhanced the production of curcumin (Kumar et al. 2014). Bacterial prodigiosins and their synthetic derivatives are effective pro-apoptotic agents against various cancer cell lines, with multiple cellular targets including multi-drug resistant cells with little or no toxicity towards normal cell lines. S. marcescens KC-1, an endophytic bacterial strain, secretes red pigment prodigiosins (Darshan and Manonmani 2015; Khanam and Chandra 2015).

Endophytic induction of secondary metabolites may be more widespread in aromatic and medicinal plants. The quality and quantity of flavor in strawberries are influenced by plant-associated methylobacteria (Verginer et al. 2010). Stenotrophomonas maltophilia (N5-18) delivered through foliar spray significantly enhanced the photosynthetic efficiency, total alkaloid and morphine content coupled with the decrease in thebaine content in Opium poppy (Pappaver sominiferum). The increase in capsule biomass and alkaloid content was followed by the consequent increase in productivity of P. sominiferum (Bonilla et al. 2014). Inoculation of Catharanthus roseus explants with endophytic Staphylococcus sciuri and Micrococcus sp. significantly enhanced the vindoline, ajmalicine and serpentine production (Tiwari et al. 2013).

Bioactive compounds produced by microbes are more convenient than plants

Bioactive compounds produced by the plants exhibit strong physiological activities. However, their production suffers from various problems including heterogeneous quality and insufficient level of productivity. Microorganisms produce primary and secondary metabolites under controlled environmental conditions assuring their maximum efficiency in uniform and high quality (Sato and Kumagai 2013). The association of plant with endophytic microorganisms has been proved as a source of materials and products with high medicinal potential as compared to the plants alone. Bioactive compounds such as secondary metabolites and enzymes synthesized by microorganisms have been extensively used as food and food supplements (Subbulakshmi et al. 2012; Mitsuhashi 2014; Wendisch 2014), pharmaceuticals (Elander 2003; Endo 2010), biofuels (Geddes et al. 2011), biopesticides (Waldron et al. 2001; Yoon et al. 2004) and detergents (Shaligram and Singhal 2010), as well as in the manufacturing process of these industrial products (Kirk et al. 2002; Merino and Cherry 2007). Metabolites and enzymes production methods have been improved since the time of their first importance was realized. B. subtilis and Lactobacillus plantarum enhanced the content of bioactive compounds (soluble phenolic compound content and antioxidant activity) in kidney bean extracts after fermentation (Limona et al. 2015).

Antimicrobial compounds

Antimicrobial metabolites produced from the endophytes are the bioactive natural compounds (Guo et al. 2008). Endophytes have developed a resistance mechanism to control pathogenic intrusion by producing secondary metabolites (Tan and Zou 2001). Many antimicrobial compounds produced by endophytes belong to several structural classes such as peptides, alkaloids, steroids, quinines, terpenoids, phenols and flavonoids (Yu et al. 2010). The novel antimicrobial metabolites from endophytes are now becoming the alternative option to overcome the increasing levels of drug resistance (Ferlay et al. 2010; Taechowisan et al. 2012). A large number of endophytic actinomycetes were isolated from 26 medicinal plants from Panxi plateau with the huge spectrum of antimicrobial activity, being the valuable reservoirs of novel bioactive compounds (Zhao et al. 2011). Endophytic 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 (Hong-Thao et al. 2016).

Nanopartcles might play a significant role as antimicrobial agents. Nanoparticles have made a significant impact on the treatment of various types of cancer. Endophytic bacteria synthesize various nanoparticles which emerges as a novel field in the research area of pharmaceutical engineering (Sunkar and Nachiyar 2012). Silver nanoparticles have antibacterial properties and act as anti-viral agent against HIV-1, hepatitis B virus, respiratory syncytial virus and herpes simplex virus (Sun et al. 2005; Taylor et al. 2005; Lu et al. 2008; Baram-Pinto et al. 2009). Endophytic strains of Bacillus sp. isolated from the medicinal plants Adhatoda beddomei (Malabar nut) and Garcinia xanthochymus (Egg tree) synthesized silver nanoparticles (AgNPs) by reduction of silver nitrate (AgNO₃) (Pissuwan et al. 2006; Kitov et al. 2008; Sunkar and Nachiyar 2012).

Anti-cancerous compounds

Several bioactive compounds produced by endophytes have been identified as anti-cancer agents (Firakova et al. 2007). Endophytic bacterial strain, EML-CAP3 isolated from C. annuum L. (red pepper) leaf, showed potent anti-angiogenic activity. This endophytic bacterial strain produced lipophilic peptides which inhibited the proliferation of human umbilical vein endothelial cells and also exhibited anti-angiogenic potential in tumor progression (Jung et al. 2015). Ginseng (Panax ginseng) is known for its ginsenosides that have anti-cancerous property. The transformed Paenibacillus polymyxa, an endophytic bacterium of Ginseng leaf, showed high ginsenoside concentration. This endophytic bacterial strain on inoculation to Ginseng plants through foliar applications combined with irrigation enhanced plant growth and the concentration of ginsenosides (Gao et al. 2015). Morphological abnormalities in the cells induced by exopolysaccharides (EPS) are the anti-tumoral mechanisms of action associated with the mitochondrial dysfunction of the treated cells. Bacillus serves a source of first discovered anti-tumoral EPS, a natural product of high therapeutic value for cancer treatment as a new anti-cancer agent (Chen et al. 2013). l-Asparaginase catalyzes the conversion of l-asparagine necessary for the function of some neoplastic cells, such as lymphoblasts. l-Asparaginase introduced to the multi-drug chemotherapy in children and adults with acute lymphoblastic leukemia resulted in significant improvement and complete remission in majority of the patients (Jakubas et al. 2008). Endophytic B. licheniformis, B. pseudomycoides and Paenibacillus denitriformis showed efficient production of l-asparaginase (Joshi and Kulkarni 2016).

Antibiotics

Antibiotics are natural compounds produced by microorganisms as secondary metabolites to kill or inhibit other microorganisms. They played an important role in twentieth century for the treatment of infectious diseases. Till now, pharmaceutical industries have primarily targeted the drugs from soil organisms, bacteria or fungi. Among the bacteria, actinobacteria are particularly noteworthy, as they produce antibiotics. Streptomyces sp. are fruitful organisms, producing ~80% of the total antibiotics (Sathiyaseelan and Stella 2011; Thenmozhi and Krishnan 2011). At least seven thousand different secondary metabolites have been discovered from Streptomyces isolates (Berdy 2005). Streptomyces synthesizes antibiotics, fungicides, modulators of the immune response, and effectors of plant growth (Hopwood 2007). Antimicrobial drugs produced by some endophytic bacteria are listed in Table 1. Endophytic Streptomyces sp. LJK109 isolated from Alpinia galangal root produces 3-methylcarbazoles which is major anti-inflammatory component and also suppresses macrophage production of the inflammatory mediators NO, PGE2, TNF-α, IL-1β, IL-6 and IL-10 in a dose-dependent manner (Taechowisan et al. 2012) (Table 1).

Table 1.

Antibiotics and drugs produced by some endophytic bacteria

Compounds	Endophytic bacteria	Biological activity	References
Ecomycin	Pseudomonas viridiflava	Anti-fungal	Miller et al. (1998)
Bacilysocin	B. subtilis 168	Anti-fungal	Tamehiro et al. (2002)
Nystatin	Streptomyces noursei	Anti-fungal	Fjaervik and Zotchev (2005)
KB425796-A	Paenibacillus sp. 530603	Anti-fungal	Kai et al. (2013)
Bacillomycin	B. subtilis, B.amyloliquefaciens	Anti-fungal, Hemolytic	Aranda et al. (2005)
Munumbicin	Streptomyces NRRL 30562	Antibacterial	Castillo et al. (2002)
Harmaomycin	Streptomyces sp.	Antibacterial	Bae et al. (2015)
Subtilin	B. subtilis	Antibacterial	Stein (2005)
Tetracyclin	Streptomyces remosus and S. aureofaciens	Antibacterial	Mark et al. (2001)
Bacteriocins	B. subtilis	Antibacterial	Sansinenea and Ortiz (2011)
Amicoumacin	B. subtilis	Antibacterial, anti-inflammatory	Pinchuka et al. (2002)
Artemisinin	Pseudonocardia sp.	Anti-malarial	Li et al. (2012)
Coronamycin	Streptomyces sp.	Anti-malarial	Ezra et al. (2004)
Spectinomycin	Streptomyces spectabilis	Anti-tuberculosis	Barry (2014)
Treponemycin	Streptomyces Strain MS-6-6	Anti-tuberculous	Mahmoud et al. (2015)
Androprostamines	Streptomyces sp. MK932-CF8	Anti-prostate cancer	Yamazaki et al. (2015)
Camptothecine	Lysinibacillus sp. and B. cereus	Anti-cancer	Singh et al. (2013)
Indolocarbazoles	Streptomyces sp.	Anti-cancer	Dong et al. (2014)
Doxorubicin	Streptomyces sp.	Treatment of Breast cancers and tumors	Brayfield (2013)
Anthracyclin	Streptomyces sp. YIM66403	Antitumor	Wei et al. (2015)
Daptomycin	Streptomyces roseoporous	Bacterial infections of skin and underlying tissues	Miao (2005)
Monensin	Streptomyces cinnamonensis	Prevent coccidiosis	Lowicki and Nski (2013)
Mytomycin C	Streptomyces caespitosus and S. lavendulae	Chemotherapeutic agent	Danshiitsoodol et al. (2006)
Saadamycin	Streptomyces sp. Hedaya48,	Anti dermatophyte	Gendy and Bondkly (2010)
Strepturidin	Streptomyces albus DSM 40763	Immunotherapy	Pesic et al. (2014)
Thaxtomin A	Streptomyces scabies	Cellulose synthesis inhibitor	Francis et al. (2015)
Xiamycin	Streptomyces sp.	Anti HIV activity	Ding et al. (2010)
β-exotoxin	B. thuringiensis	Insecticidal	Espinasse et al. (2002)
Albaflavenol B	Streptomyces sp.	As sesquiterpene	Raju et al. (2015)

The majority of endophytic bacteria produce different kinds of antibiotics. Ecomycin, pseudomycins and kakadumycins are some of the novel antibiotics produced by endophytic bacteria (Christina et al. 2013). Pseudomonas viridiflava, an epiphyte or endophyte of the leaves of many grasses, produced ecomycin, which is used for the treatment of respiratory and urinary tract infections, skin, eye and gut Infections. The structure of ecomycin incorporates some unusual amino acids such as homoserine and beta-hydroxyaspartic acid, besides common amino acids alanine, serine, threonine and glycine (Miller et al. 1998). Naphthomycin K, a chlorine-containing ansamycin, showed cytotoxicity against P388 and A-549 cell lines. Endophytic Streptomyces sp. CS synthesized 24-demethylbafilomycin C1, a member of bafilomycin, which targets both autophagy and apoptosis pathways in pediatric B cell acute lymphoblastic leukemia (Li et al. 2010; Qin et al. 2011; Yuan et al. 2015). Endophytic Streptomyces sp. isolated from Aucuba japonica and Cryptomeria japonica produced two new novobiocin analogs and cedarmycins, respectively. A new naphthoquinone antibiotic, alnumycin was also isolated from the endophytic Streptomyces sp. from Alnus glutinosa. Streptomyces sp. NRRL30562, an endophyte of snake vine plant, produced new peptide antibiotic, munumbicins A-D40 with a broad spectrum activity against several human diseases, phytopathogenic fungi and bacteria. Endophytic Streptomyces sp. NRRL30566 isolated from a fern-leaved grevillea (Grevillea pteridifolia) tree produced kakadumycin which is chemically related to echinomycin (Castillo et al. 2003).

Future prospective

As our understanding of endophytic bacteria continues to grow, the potential to exploit their unique characteristics of bioactive compound synthesis alone or with plants is also increasing day by day. The plant benefits enhanced by combined application of beneficial microorganisms in the form of bio-fertilizer have become an alternative tool for organic farming. Exploitation of endophytic bacteria as a plant growth-promoting agent further necessitates our ability to understand and utilize bacterial endophytes in agriculture under integrated bio-fertilizer technology programme. How endophytes modulate the physiology of plant and its metabolism and how they use the intermediary substances of primary and secondary metabolism as nutrition and precursor to produce either novel compounds or enhance the existing important secondary metabolites are still largely unknown.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this manuscript.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.