Abstract
Endophytes are microorganisms that reside in internal tissues of living plants without causing any negative effect. These offer remarkable potential for the exploitation of novel and eco-friendly secondary metabolites used in medicine, pharmaceutical industry, and agriculture. This chapter is focused on diversity in bioactive compounds of endophytic fungi, actinomycetes, and bacteria. Endophytes as novel source of potentially useful medicinal compounds are discussed along with the need to search for new and more effective agents from endophytes to combat disease problems.
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4.1 Introduction
Endophytes are microbes (fungi or bacteria) that live within the plant tissues without causing any noticeable symptoms of disease (Tejesvi et al. 2007). Endophytes invade the tissues of living plants and reside between living plant cells (Vanessa and Christopher 2004). Some form a mutually beneficial relationship (symbiosis) with the host plants while others are opportunistic pathogens. Petrini et al. (1992) reported that there may be more than one type of mycoendophytes found within a single plant. For example, 13 taxa of mycoendophyte were isolated from the leaf, stem, and root tissues of Catharanthus roseus (Kharwar et al. 2008).
It is reported that fungal metabolites are not only indispensable for medicine but also important for plant protection. The demand for new highly effective agricultural agents to control farm pests and pathogens is huge, and partly arises from the removal of synthetic compounds from the market because of their toxicity toward the environment. Shipunov et al. (2008) tested the co-introduction and host-jumping hypotheses in plant communities by comparing endophytes isolated from the invasive spotted knapweed (Centaurea stoebe, Asteraceae) in its native and invaded ranges. Shipunov et al. (2008) reported that endophytes can affect the competitiveness of C. stoebe. Both co-introduction and host-jumping of endophytes align with hypotheses of plant invasion that are based on enhanced competitiveness. Kharwar et al. (2008) reported 183 mycoendophytes representing 13 fungal taxa isolated from leaf, stem, and root tissues of C. roseus from two sites representing two different ecosystems in North India. The leaf tissues showed more diversity of endophytes such as Drechslera, Curvularia, Bipolaris, Alternaria, and Aspergillus sp. Wei et al. (2009) studied the colonization frequencies of endophytic Pestalotiopsis species diverse with host plants, ages, tissues, and sites. Ya-li et al. (2010) reported 49 endophytic fungi which were recovered from Saussurea involucrata and identified using morphological and molecular techniques. Among these fungi Cylindrocarpon sp. was the dominant species followed by Phoma sp. and Fusarium species. Li and Shun (2009) reported the recovery of 300 isolates in which 172 isolates were from Dracaena cambodiana and 128 from Aquilaria sinensis.
4.2 Fungal Endophyte Diversity and Bioactive Compounds
The maximum biological diversity in terrestrial ecosystems is in tropical and temperate rainforests. Interestingly, they also have the greatest number of mycoendophytes. These ecosystems cover only 1.44 % of the land’s surface, yet they harbor more than 60 % of the world’s terrestrial biodiversity (Strobel and Daisy 2003). Hazalin et al. (2009) isolated 300 endophytes from various parts of plants collected from the National Park, Penang in Malaysia. Some of these endophytes demonstrated cytotoxic activity against the murine leukemic P388 cell line and 1.7 % against a human chronic myeloid leukemic cell line K562 (Hazalin et al. 2009). Survey of the literature provides evidence of increasing research on endophytes and their secondary metabolites. Studies on medicinal plants used by indigenous communities to treat various diseases have resulted in a wealth of scientific discoveries.
Fungal endophytes are being increasingly accepted as an ecological group of microorganisms that may provide sources for new secondary metabolites with useful biological activities. An array of active principles has been isolated and characterized from endophytes and many of these have diverse bioactivities (anticancerous, antioxidants, antifungal, antibacterial, antiviral, anti-insecticidal, and immune suppressants). Isolation of endophytic fungi from coffee plants (Coffea arabica and C. robusta) was shown to have antimicrobial activity against various human pathogenic bacteria (Sette et al. 2006). At present, there is an urgent need to search for endophytic metabolite that can be developed as safe, effective antifungal agents that are nonpetrochemical, eco-friendly, and easily obtained (Liu et al. 2006). Endophyte Taxomyces andreanae, which produces taxol in vitro, was isolated from Taxus sp. (Stierle et al. 1993). Vennila et al. (2010) studied the effect of taxol extracted from the endophytic fungus Pestalotiopsis pauciseta recovered from Tabebuia pentaphylla Hems. T. pentaphylla (family Bignoniaceae) is distributed in Northern Mexico, Southern Florida, and Cuba.
Zhou et al. (2010) summarized the recent advances in taxol-producing endophytic fungi all over the world. Kajula et al. (2010) studied the extracellular siderophore production as well as production of antibacterial and antioxidant compounds by endophytic fungi of Scots pine (Pinus sylvestris L.) and Labrador tea (Rhododendron tomentosum Harmaja). The pinolenic acid contained in pine nut oil helps curb appetite. It is used as a pain reliever in arthritis, aches, and sore muscles. Yang et al. (1994) reported that the phenol and phenolic acids detected in culture medium of endophytes often have remarkable biological activities. 2-Hydroxy-6-methylbenzoic acid was isolated from endophytic Phoma species which showed noteworthy antibacterial activity. Phoma medicaginis exists as a prolonged asymptomatic infection of its host plant (Medicago species). Suryanarayanan et al. (2005) studied the cactus Cylindropuntia fulgida for its endophytic diversity. The authors reported 900 endophytic isolates belonging to 22 fungal species from 21 cactus sp.
Karsten et al. (2007) reported herbicidal and algaecidal activity in ethyl acetate extract of an endophytic Phoma sp. isolated from Fagonia cretica, as ethnomedicine, F. cretica is used against fever, thirst, vomiting, dysentery, asthma, urinary discharges, liver trouble, dropsy, delirium, typhoid, toothache, stomach troubles, and skin diseases. Randa et al. (2010) isolated a Botryosphaeria rhodina from the stem of the medicinal plant Bidens pilosa (Asteraceae) that showed anti-inflammatory, antiseptic, and antifungal effects. Borges and Pupo (2006) reported two novel hexahydroanthraquinone derivatives, dendryol E and F isolated from Phoma sorghina, which was found as endophyte in association with the medicinal plant Tithonia diversifolia.
Schwarz et al. (2004) optimized the culture conditions of Phoma species and reported highest nematicidal activity in yeast malt glucose medium. Phomodione, 2,6-diacetyl-7-hydroxy-4a,9-dimethoxy-8,9b-dimethyl-4a.9b-dihydrodibenzo furan-1,3, an usnic acid derivative, was isolated from culture broth of a Phoma species which was an endophyte in the Guinea plant (Saurauia scaberrinae). Smith et al. (2008) provided direct evidence from bioassays of endophytes isolated from tropical plants and bioinformatic analyses that will give a novel chemistry of potential value. Raviraja (2005) studied 18 species of mycoendophytes, isolated from bark, stem, and leaf segments of five medicinal plant species growing within the Kudremukh range in the Western Ghats of India. The most common endophytic fungi were Curvularia clavata, C. lunata, C. pallescens, and Fusarium oxysporum. The greatest species richness and frequency was found in the leaf segments, rather than the stem and bark segments of the host plant species. Thus, if endophytes could produce the same rare and important bioactive compounds as their host plants, this would not only reduce the need to harvest slow-growing and possibly rare plants but also help to preserve the world’s ever-diminishing biodiversity.
Large number of eco-friendly drugs produced by fungal endophytes is large as compared to endophytic bacteria and actinomycetes. Natural products from fungal endophytes can be grouped into several categories, including alkaloids, steroids, terpenoids, isocoumarins, quinones, phenylpropanoids and lignans, phenol and phenolic acids, aliphatic metabolites, lactones, etc. Zhen-Liang et al. (2011) reported novel bioactive compounds with spiro-5, 6-lactone ring skeleton isolated from endophyte Massrison sp. which is recovered from wild Rehmannia glutinosa. Further, they performed the antifungal and cytotoxic activities of the compounds. Debbab et al. (2009) reported secondary metabolites in Chaetomium sp. isolated from Salvia officinalis and evaluated their cytotoxic activity. Rukachaisirikul et al. (2007) reported endophytic Phomopsis species which produces secondary metabolites such as phomoenamide, phomonitroester, and deacetylphomoxanthone, and showed antibacterial activity against Mycobacterium tuberculosis. Tuberculosis (TB) infections are continuously increasing. Gordien et al. (2010) studied extracts from Scottish plants, lichens, and mycoendophyte which were screened for activity against Mycobacterium aurum and M. tuberculosis. The greatest activity against M. aurum was shown by extracts of Juniperus communis roots of the lichen Cladonia arbuscula and of a mycoendophyte isolated from Vaccinium myrtillus (Gordien et al. 2010). It is obvious that mycoendophytes serve as a source of potentially useful medicinal compounds. For example, 3-Nitropropionic acid was isolated from Phomopsis species which inhibited Mycobacterium tuberculosis (Copp and Pearce 2007). Guo et al. (2008) studied the new antimicrobial metabolites isolated and extracted from the culture of Colletotrichum species from Artemisia annua, which is a traditional Chinese herb. It is well recognized for its synthesis of artemisinin (Antimalarial drug).
4.3 Endophytic Actinomycetes
The actinomycetes that reside in the tissues of living plants and do not visibly harm the plants are known as endophytic actinomycetes (Strobel et al. 2004). Endophytic actinomycetes exist in the inner tissues of living plants. They have been isolated from the stem, leaf, fruit, root, and interior of other parts of many plants species (Okazaki et al. 1995; de Araújo et al. 2000; Coombs and Franco 2003). These organisms have attracted taxonomists, agronomists, chemists, ecologists, and evolutionary biologists. It has been indicated by numerous studies that these prolific actinomycetes appear to have a capacity to produce an impressive and important array of secondary metabolites. These metabolites exhibit a wide range of biologically active compounds, such as antibiotics, antitumor, anti-infectives, and other important chemical agents, such as plant growth promoters and enzymes. Similarly, actinomycetes also contribute to their host by promoting growth and enhancing their ability of withstanding in unfavorable environmental conditions (Qin et al. 2011a, b). Moreover, it represents under explored reservoir of novel species of potential interest in the discovery of novel lead compounds and for exploitation in pharmaceutical, agriculture, and industry (Qin et al. 2009a, b).
The actinomycetes accounts for a high proportion of soil microbial diversity and contains the most economically significant prokaryotes, producing about half of the known bioactive compounds (Lazzarini et al. 2000), including antibiotics (Bérdy 2005), antitumor agents (Cragg et al. 2005), immunosuppressive agents (Mann 2001), and enzymes (Oldfield, 1998). Endophytic actinomycetes have attracted attention in recent years, with increasing reports of isolates from a range of plant types, including medicinal plants (Taechowisan et al. 2003; Zin et al. 2007) and crop plants (cereals, such as wheat and rice, as well as potatoes, carrots, tomatoes, and citrus) (Nejad and Johnson 2000; Araújo 2002; Coombs and Franco 2003; Surette et al. 2003; Sessitsch et al. 2004; Tian et al. 2007). Endophytic actinomycetes promote the growth of host plants as well as to reduce disease caused by plant pathogens through various mechanisms, including the production of secondary metabolites, which are used in direct antagonism against plant diseases and pests (Cao et al. 2004, 2005; Castillo et al. 2007), also changes in host physiology (Igarashi et al. 2002), and the induction of systemic acquired resistance in plants (Conn et al. 2008). Similarly, other metabolites have antibiotic activity, suggesting that these organisms can be an important source for bioprospecting. Day-by-day the new species of endophytic actinomycetes have been increasingly reported. Thus, these endophytes are expected to be potential sources of new species with new bioactive agents (Gu et al. 2006; Duangmal 2008).
Higher plants contain a promising niche inside their tissues. The studies have demonstrated that some actinomycetes can form important associations with plants and colonize themselves in their inner tissues. For example, Frankia species and Streptomyces scabies important actinomycetes can penetrate their respective hosts and establish a relation as either endophyte or pathogen (Benson and Silvester 1993; Doumbou et al. 1998). The actinomycetes that live within the tissue of living plants and do not cause any symptom or do not visibly harm the plants are known as endophytic actinomycetes (Stone et al. 2000). It is suggested that there are approximately 300,000 plant species on the Earth, and each plant is considered to be the host for one or more type of microbial endophytes (Strobel and Daisy 2003), which creates an enormous biodiversity of endophytic microorganisms. But, a few of these endophytic actinomycetes associated with plants have been studied, indicating the opportunity to find new species and new related natural products among plants living in different niches and ecosystems. Recent studies revealed that large group of endophytic actinomycetes species and their diverse compounds with different biological functions are present (Araujo et al. 2002; Coombs and Franco 2003; Ryan et al. 2008; Bascom-Slack et al. 2009). But in some cases, actinomycetes act as biological agents (Cao et al. 2005) that enhance the plant growth promotion activity (Igarashi et al. 2002) and promote plant development in adverse environmental conditions (Hasegawa et al. 2006). These organisms are relatively unstudied and are potential sources of novel natural products used in medicine, agriculture, and industry (Strobel et al. 2004). Continuously, new findings in the recent study of the endophytic actinomycetes have an enormous biotechnological potential in the areas of natural products discovery and related applications.
Moreover, the natural products play highly significant role in drug discovery and development process. Cragg (2005) reported that 28 % of the new chemicals were discovered and 42 % of these chemicals were natural products and their derivatives, including anticancerous drugs. More than 22,000 biologically active metabolites were recovered from microorganisms, out off these 45 % compounds were recovered from actinomycetes, such as Streptomyces which is an excellent producer (Bérdy 2005). The application of actinomycetes for health and well-being of people throughout the world is a revolution in medicine (Demain and Sanchez 2009).
4.3.1 Diversity of Endophytic Actinomycetes in Medicinal Plants
Medicinal plants play a very important role in medicine to cure different types of diseases. In 1886, the genus Frankia was isolated from non-legume root nodules, which indicate the association between actinomycetes and host (Okazaki 2003). In the last two decades, endophytic actinomycetes have been isolated from all examined vascular plants, ranging from woody trees to herbaceous plants. The symbiotic colonization of terrestrial plants by actinomycetes is ubiquitous and common in nature. Therefore, the endophytic actinobacteria are important components of microbial biodiversity because of the frequent plant species. The plants which maintain the ethnobotanic values it is considered as promising sources of endophytes which produce novel bioactive compounds.
Endophytic actinomycetes also reported from crop plants, such as wheat, rice, potato, carrots, tomato, and citrus (Nejad and Johnson 2000; Araujo et al. 2002; Coombs and Franco 2003; Surette et al. 2003; Sessitsch et al. 2004; Tian et al. 2007; Velazquez et al. 2008), woody tree species (Taechowisan et al. 2003; Zin et al. 2007; Yuan et al. 2008; Zhao et al. 2010a, b, c), mosses, and ferns (Janso and Carter 2010). This study reported that the greatest diversity of endophytes is probable to occur in the tropical and temperate regions (Strobel and Daisy 2003). The occurrence of actinomycetes in roots compared to other tissues is common. Taechowisan et al. (2003) screened 5,400 roots, leaves, and stem tissues from 36 species of plants and recovered 212 isolates from roots, 97 from leaves, and 21 from stems. Furthermore, Verma et al. (2009a, b) recovered more than double the number of all isolates from roots than from stems or leaves from 20 different Indian lilac trees and Azadirachta indica. Root plays a vital role for water and nutrient uptake for plants, and therefore it is an ideal substrate for actinomycete colonization (Janso and Carter 2010).
Endophytic actinomycetes diversity and antibiotic activity was reported recovered from medicinal plants of tropical regions (Li et al. 2008a, b; Bascom-Slack et al. 2009; Qin et al. 2009a). Qin et al. (2009b) reported 2,174 endophytic actinomycetes isolated from different medicinal plants of tropical rainforest of China. Among these only from one kind of plant, Maytenus austroyunnanensis, one new genus, and seven new species of endophytes were isolated. The richness of actinomycetes and their diversity from tropical rainforest are much higher compared to biogeographical regions. Similarly, tropical rainforest has a promising potential as a source of actinomycetes and new endophytes. It is reported that the endophytic actinomycetes are diverse and the diversity may vary between different host plant regions and different plant species.
Taechowisan et al. (2003) isolated 330 endophytes from different medicinal plants belonging to four different genera (Streptomyces, Microbispora, Nocardia and Micromonospora). Also El-Shatoury et al. (2009) reported endophytic actinomycetes associated with the medicinal plant, Achillea fragrantissima (Forssk) Sch. Bip. (Compositae), of Saint Katherine, South Sinai, Egypt. The diversity of endophytic actinomycetes showed no significant differences between different locations of the studied regions. Twenty-five isolates were identified and categorized into seven genera of actinomycetes (viz. Streptomyces, Nocardioides, Kitasatosporia, Nocardia, Kibdelosporangium, Pseudonocardia, and Promicromonospora). In addition to these one unidentified isolate was also obtained. Genera Nocardia and Streptomyces were the most recorded in A. fragrantissima internal tissues. An endophytic actinomycete was recovered from four medicinal plants such as Artemisia herba-alba, Echinops spnosus, Mentha longifolia, and Ballota undulata belonging to different genera. Among these the Streptomyces species was dominant as compared to other (El-Shatoury et al. 2006). An endophytic actinomycete novel species Pseudonocardia endophytica sp. nov. was isolated from the inner tissues of the traditional Chinese medicinal plant Lobelia clavata by Chen et al. (2009). Wang et al. (2008) reported the diversity of uncultured microbes associated with medicinal plant Mallotus nudiflorus and found that actinomycetes were the most dominant microbial group, covering about 37.7 % of whole endophytes isolated. Glycomyces endophyticus sp. nov. is an endophytic actinomycete, designated strain YIM 56134T, isolated from the root of a Chinese medicinal plant, Carex baccans Nees, collected from Yunnan, South West China. This medicinal plant harbors other endophytic actinomycetes in their internal tissues (Qin et al. 2008).
The diversity of endophytic actinomycetes associated with tropical, native plants is essentially unexplored. Janso and Carter (2010) isolated 123 endophytic actinomycetes from tropical plants collected from several locations in Papua New Guinea, Mborokua Island, and Solomon Islands. These isolates were found to be prevalent in roots but uncommon in leaves. Characterization of 105 isolates of unique strains by 16S rRNA gene sequence analysis revealed that 17 different genera were represented and rare genera also, such as Sphaerisporangium and Planotetraspora, which have never been previously reported to be endophytic. Phylogenetic analyses grouped many of the strains into clades distinct from known genera within Thermomonosporaceae and Micromonosporaceae, indicating that they may be unique genera. Although Streptomyces was the most frequently isolated genus, the Streptosporangiaceae was also well-represented family, which consisted of five different genera: Sphaerisporangium, Planotetraspora, Nonomuraea, Streptosporangium, and Microbispora. Planotetraspora and Sphaerisporangium were common among rare genera of actinomycetes and were consistently represented in plants from each sampling location. Also Microbispora, which belongs to Streptosporangiaceae, is common in a variety of plants. They gave new report on the occurrence of Planotetraspora and Sphaerisporangium in plants as endophytes. Also three Kibdelosporangium strains, from the roots of a Heterospathe sp. and Pandanus sp., are the first report of endophytes isolated from these genera (Janso and Carter 2010).
Zhu et al. (2009) isolated more than 160 endophytic actinomycetes from multiple tissues of both wild and cultured specimens of the native, tropical tree Trewia nudiflora. They reported the presence of actinomycetes from each tissue, provided relatively little information on the biodiversity of these isolated actinomycetes, and characterized only Streptomyces sp. Castillo et al. (2007) isolated endophytic actinomycetes from plant species growing in Southern Patagonia, but they only recovered Streptomyces sp. from the stems. Pseudonocardia sichuanensis sp. nov., a novel endophytic actinomycetes has been isolated from the root of Jatropha curcas L. (Qin et al. 2011a, b). Three novel endophytic Streptomyces have been isolated from plants with ethnobotanical properties on the Malay Peninsula including Thottea grandiflora (Aristolochiaceae), Polyalthia sp. (Annonaceae), and Mapania sp. (Cyperaceae) (Zhao et al. 2007; Zin et al. 2007). Traditional Chinese medicinal plants are large sources of biologically active compounds, providing raw material for agriculture, pharmaceutical, cosmetics, and fragrance industries. The endophytes of these medicinal plants take part in biochemical pathways and produce analogous or novel bioactive compounds. In a study, 560 endophytic actinomycetes were isolated from 26 medicinal plant species in Panxi plateau. According to the phyllogenetic analysis, seven isolates were Streptomyces sp., while the remainder belonged to genera Micromonospora, Oerskovia, Nonomuraea, Promicromonospora, and Rhodococcus (Zhao et al. 2011).
4.3.2 Bioactive Compounds from Actinomycetes
Endophytic Actinomycetes of medicinal plants participate in metabolic pathways of medicinal plants and produce analogous or novel bioactive compounds, for example taxol (Strobel et al. 1999). Endophytic actinomycetes are considered as rich and potential sources of novel bioactive compounds and various bioactive compounds are continuously isolated from them until now (Taechowisan et al. 2005; Castillo et al. 2006; Igarashi et al. 2007a, b). Endophytic actinomycetes associated with medicinal plants could be a rich source of functional metabolites (Strobel et al. 2004). Natural products from endophytes is evident from the number of review articles that have appeared in the recent literatures (Hasegawa et al. 2006; Zhang et al. 2006; Gunatilaka 2006; Guo et al. 2008; Staniek et al. 2008; Ryan et al. 2008; Verma et al. 2009a, b). Study of the endophytic actinomycetes has resulted in the identification of many new natural products with wide range of biological activities.
Endophytic actinomycetes, mainly from medicinal plants, show the ability to inhibit or kill a wide variety of harmful microorganisms such as pathogenic bacteria, fungi, and viruses. Thus, there is great application value to develop antimicrobial drugs from endophytic actinobacteria. Till now, number of new antibiotics have been isolated, such as kakadumycins (Castillo et al. 2003), celastramycins A-B (Pullen et al. 2002), munumbicins A-D (Castillo et al. 2002), and demethylnovobiocins (Igarashi 2004). This was observed from the culture broth of some endophytic Streptomyces sp. a simple compound 6-prenylindole was isolated. This chemical exhibited a significant antifungal activity against plant pathogen Fusarium oxysporum. The chemical was originally isolated from the plant liverwort (Hepaticae). This compound is isolated from both plant and endophyte (Igarashi 2004). From the strain Streptomyces sp. TP-A0456 two novel compounds cedarmycins A and B were isolated, which were also isolated from a twig of cedar. The Cedarmycins A showed antifungal activity against Candida glabrata in vitro (Igarashi 2004). Another endophytic Streptomyces sp. Tc022 isolated from Alpinia galanga strongly inhibited the fungi Colletotrichum musae and Candida albicans. The metabolites extracted from Streptomyces sp. Tc 022 in the broth culture medium showed the presence of a major component actinomycin D, which displayed strong antifungal activity (Taechowisan et al. 2006). Two new chromophoric peptides antibiotics designated as munumbicins E-4 and E-5 were isolated from endophytic Streptomyces NRRL 30562 which produces broadspectrum antibiotics such as munumbicins A-D. These compounds showed broadspectrum activity against both Gram-positive and Gram-negative bacteria (Castillo et al. 2006). Recently, a new antifungal compound saadamycin was isolated from endophytic Streptomyces sp. Hedaya48, it confers potent antifungal activity against clinical fungi such as dermophytes, etc. (El-Gendy and EL-Bondkly 2010). These studies suggest that actinomycetes possess strong microbial compounds, which are utilized as drugs and can be modified to combat the future challenges by use of biotechnological approaches.
Nowadays, there has been an increasing interest in discovering antitumor agents from endophytes. Endophytic actinomycetes live in close association with their host plants and close relationship with them, then it becomes a real possibility that genes involved in natural products biosynthesis could be exchanged via horizontal gene transfer between endophytic actinomycetes and plants, resulting in synthesis of plant-derived compounds by a microbial endophyte such as the paclitaxel-producing Kitasatospora sp. isolated from Taxus baccata in Italy (Caruso et al. 2000; Janso and Carter 2010). This is the first report on synthesis of taxol from endophytic actinomycetes. Also, maytansinoids (19-membered macrocyclic lactams ansamycin antibiotics), a potent antitumor agent related to antitumor chemical compounds that were originally isolated from members of the higher plant families Celastraceae, Rhamnaceae, and Euphorbiaceae (Kupchan et al. 1972; Powel et al. 1982) and some mosses (Suwanborirux et al. 1990), were also produced by plant-associated actinomycete Actinosynnema pretiosum (Higashide et al. 1977). One novel chlorine-containing ansamycin, namely naphthomycin K, was obtained from the endophytic strain of Streptomyces sp. CS was isolated from Maytenus hookeri a medicinal plant producing maytansinoids. This compound showed cytotoxic activity against P388 and A-549 cell lines (Lu and Shen 2007). It was quite interesting that the ansacarbamitocins, a new family of maytansinoids, were isolated from an actinomycete strain Amycolatopsis CP2808 that belongs to the family Pseudonocardiaceae; also, the ansamitocin-producing strain A. pretiosum belongs to the same family (Snipes et al. 2007). The 24-demethylbafilomycin C1, newly added member of the afilomycin subfamily, and two more new bafilomycin derivatives were isolated from the strain Streptomyces sp. (Lu and Shen 2003, 2004).
In the subsequent research in the field of antitumor by researchers all over found new bioactive chemical compounds including five 16-membered macrolides, belonging to the bafilomycin subfamily were isolated from Streptomyces sp. CS. was isolated from M. hookeri and showed cytotoxic activity against MDA-MB-435 cell line in vitro (Li et al. 2010). Another strain Streptomyces sp. ls9131, which was also isolated from M. hookeri, produced novel macrolides. This compound dimeric dinactin had strong antineoplastic activity and antibacterial activity (Zhao et al. 2005). Two novel compounds anthraquinones and lupinacidins A and B were isolated from the fermented broth of newly identified endophytic actinomycetes, Micromonospora lupine. The lupinacidins showed considerable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells (Igarashi et al. 2007a, b). Kim et al. (2006) isolated two new 6-alkylsalicylic acids, salaceyins A and B from another strain Streptomyces laceyi MS53. Salaceyins A and B showed cell toxicity against human breast cancer cell line SKBR3. Pterocidin is a new antitumor cytotoxic chemical compound, isolated from the endophytic Streptomyces hygroscopicus TP-A0451 exhibited cytotoxicity against cancer cell lines (Igarashi et al. 2006). Two compounds 5, 7-dimethoxy-4-phenylcoumarin and 5, 7-dimethoxy-4-p-methoxylphenylcoumarin isolated from endophytic Streptomyces aureofaciens CMUAc130 were originally produced by numerous species of plants. These bioactive compounds showed high and strong antifungal and antitumor activity (Taechowisan et al. 2005, 2007a). These findings support the application of them as anti-inflammatory agent (Taechowisan et al. 2007b). From the endophytic strain Streptomyces sp. SUC1, four novel secondary metabolites, lansai A to D were isolated. Tuntiwachwuttikul et al. (2008) reported lansai B which showed weak activity against the BC cell line, lansai C also showed significant anti-inflammatory activity in LPS-induced RAW 264.7 cells. In a word, endophytic actinobacteria still remain a relatively untapped source of novel natural products, presumed to push forward the frontiers of drug discovery against deadly cancers.
Endophytic actinomycetes also produced various other different bioactive compounds with a large magnitude of functioning. An endophytic Streptomyces sp. isolated from a Chinese traditional medicine plant Cistanche deserticola produced tyrosol. This compound acts as a new possible ligand for GPR12 (Lin et al. 2008). Coronamycin is a complex of novel peptide antibiotics extracted from verticillate Streptomyces sp. isolated from an Epiphytic vine, Monstera sp., which shows activity against pythiaceous fungi and the human fungal pathogen Cryptococcus neoformans. It also shows activity against the malarial parasite Plasmodium falciparum. It also showed antifungal activity against human fungal pathogen Cryptococcus neoformans (Ezra et al. 2004). Endophytic actinomycetes associated with higher plants, particularly with medicinal plants (used traditional medicines), are harboring bioactive compounds with medicinal properties; it is supported by the examples of taxol and maytansinoids discussed above. Endophytic actinomycetes as a key player of biocontrol agents have been partly discussed (Hasegawa et al. 2006). Studies are continuously conducted to unravel the mechanisms of action of these endophytes for production of bioactive compounds, such as antibiotics and cell wall degrading enzyme (El-Tarabily and Sivasithamparam 2006).
4.4 Bacterial Endophytes
The survival of endophytic bacteria inside different plant tissues is a well-predictable phenomenon (Sharrock et al. 1991; Fisher et al. 1992; McInroy and Kloepper 1995a, b). In general, endophytic bacteria are described as bacteria that are able to colonize the living plant tissues without harming a plant (Kado 1992). Endophytic bacteria isolated from the internal plant tissue of healthy plants comprises over 129 species representing over 54 genera, with Pseudomonas, Bacillus, Enterobacter, and Agrobacterium being the most commonly isolated bacterial genera (Mundt and Hinkle 1976; Gardener et al. 1982; Sturz 1995; McInroy and Kloepper 1995a; Hallmann et al. 1997a, b; Mahafee and Kloepper 1997).
Endophytic bacteria are usually isolated from the rhizosphere (roots), seeds, or plant material (leaf, branch, and other parts of plant) (Hallmann et al. 1997a, b). A division of rhizobacteria may enter the interior of the root by hydrolyzing cell wall cellulose, through tumors, along water flow, through wounds, or through lateral branching sites (Hallmann et al. 1997a, b; Siciliano et al. 1998). Evidences of plant-associated microbes has been discovered in the fossilized tissues of stems and leaves and these endophytic relationships may have begun from the time that higher plants first have appeared on the Earth, hundreds of millions of years ago to establish these types of relationships (Taylor and Taylor 2000). As a result of these associations between bacteria and plants, there is possibility to happen that some of these endophytic bacteria modified their genetic systems allowing for the transfer of information between themselves and the higher plant and vice versa (Stierle et al. 1993). The endophytic bacteria are known to contribute to the host plants growth and development by producing plant growth regulators. The bacterial endophytes are also known to increase host plants resistance to plant pathogens and parasites to promote biological nitrogen fixation and to produce antibiotics. The major group of endophytic bacteria comes under the category of actinomycetes, which are mostly studied and established group of endophytic bacteria. In the next section we will be confined to the endophytic bacteria other than Endophytic actinomycetes, which have already been discussed above.
4.4.1 Diversity of Endophytic Bacteria in Medicinal Plants
Various researchers reported endophytic microbes from various plants either medicinally useful or not. Nearly 300,000 plant species that exists on the earth and each individual plant is host to one or more endophytes. Only a few these plants have ever been completely studied for their endophytic nature. Consequently, the opportunity to find new and interesting microorganism among myriads of plants in different ecosystems is great (Strobel and Daisy 2003). Endophytic bacteria are commonly associated with medicinal plants.
Based on the visible morphological differences totally 20 bacterial isolates were isolated from Andrographis paniculata plant samples in India. Among all these 20 endophytic bacterial isolates, 11 were Gram-positive cocci and nine Gram-positive rods. Total seven isolates showed positive result for endospore staining and they were suspected as Bacillus species. The other isolates could not be identified (Arunachalam and Gayathri 2010). Cho et al. (2002) reported a strain of Bacillus CY22 from the roots of Balloon flower Platycodon grandiflorum in Republic of Korea. This was the endophytic bacterium capable of secreting various biologically active compounds showing activity against various pathogenic bacteria and fungi. A total of 98 isolates of bacterial endophytes were obtained from 27 medicinal plants by Berde et al. (2010). Among these isolates 58.43 % were Gram-positive rods, 19.10 % were Gram-negative rods, 10 % Gram-positive, and 10 % Gram-negative cocci. Bhore et al. (2010) screened three bacterial endophytes Pseudomonas resinovorans, Paenibacillus polymaxa, and Acenitobacter calcoaceticus from the leaves of Sambung Nyawa [Gynura procumbens (Lour.) Merr.].
The species Jacaranda decurrens Cham. is a shrub present in diverse physiognomies of the Brazilian Cerrado, popularly described as a medicinal plant that acts in gynecological infections, Giardia and amoeba’s diseases, and as an antisyphilitic. A total of 18 isolates of endophytic bacteria were isolated from Jacaranda decurrens Cham. with predomination of the bacteria of the genera Bacillus (39 %), Pseudomonas (27.6 %), Corynebacterium (16.7 %), Actinomyces (11.1 %) and Staphylococcus (5.6 %) (Carrim et al. 2006). In a study, Laorpaksa et al. (2008) screened 106 isolates of endophytic bacteria from 35 Thai medicinal plants. These endophytic bacteria belong to the diverse genera of bacteria, most of these endophytic bacteria showed antimicrobial properties against bacterial and fungal human pathogens.
The diversity of endophytic bacteria associated with ginseng (Panax ginseng C.A. Meyer) plants of varying age levels in Korea was investigated. A total of 51 colonies of endophytic bacteria were isolated from the interior of ginseng stems. These endophyte communities recovered from ginseng plant based on the results of 16S rDNA analysis, Bacillus and Staphylococcus, were dominant in age group 1–4-year-old plants. Other bacteria such as Pseudomonas, Agrobacterium, and Stenotrophomonas, Mycobacterium Paenibacillus, and Staphylococcus also being predominant genera (Vendan et al. 2010).
Echinacea is one of the most popular herbal supplements and the popularity of this remedy is due to its use for the treatment of infections and its immune-stimulatory and anti-inflammatory effects (Giles et al. 2000). Thirty-nine isolates of endophytic bacteria were isolated and selected based on colony morphology from four different micropropagated species of Echinacea (20 isolates from E. pallida var. angustifolia, four from E. pallida var. pallida, seven from E. purpurea, and eight isolates from E. pallida var. tenneseensis). These isolates mainly include Bacillus pumilus (from E. purpurea), Acinetobacter lwofii and Stenotrophomonas maltophila (from E. pallida var. angustifolia), Bacillus pumilus (from E. pallida var. pallida), Pseudomonas stutzeri, and Wautersia paucula (from E. pallida var. tenneseensis). W. paucula was previously known as Ralstonia paculua (Lata et al. 2006).
4.4.2 Chemical Diversity of Endophytic Bacteria
The need for new and useful compounds to provide resistance and relief in all aspects of human conditions is continuously over growing. Natural products have been the traditional pathfinder compounds offering an untold diversity of chemical structures (Strobel and Daisy 2003). The word Bioprospecting is today most commonly used to express the collection and screening of biological material for commercial purposes (Synnes 2007). Molecules derived from natural products, particularly those products by plant and microbes, have an excellent record of providing novel chemical structural compounds for development of new pharmaceutical products. It was not until Pasteur discovered that fermentation is caused by living cells that people seriously began to investigate microorganisms as a source of high value metabolites. Since then people have been engaged in the discovery and application of microbial metabolites with the activity against both plant and human pathogens. Further, most of the discovery of plethora of microbes for application that span a broad spectrum of utility in medicine, agriculture, and industry is now practical (Balagurunathan and Radhakrishnan 2007).
Bacterial endophytes are mostly responsible for the production of the chemical metabolites which are used by the plants for their growth and development, against pathogens, etc. Apart from these functional metabolites which are utilized by plants, these endophytic bacteria also produce chemicals which are having pharmaceutical functions such as antibacterial, antifungal, anticancer, and many more biological activities. Bhore et al. (2010) screened cytokinin and cytokinin-like compounds from the endophytic bacteria (Pseudomonas resinovorans, Paenibacillus polymaxa, and Acenitobacter calcoaceticus) isolated from the medicinal plant Gynura procumbens (Lour.) Merr. resulted in growth and development of the host plant. In a study, Carrim et al. (2006) reported proteolytic, amilolytic, lipolytic, and esterasic activity showing enzymes from isolates of endophytic bacteria isolated from the Jacaranda decurrens Cham. a medicinal plant. All these enzymes are of biotechnological and pharmaceutical interest used for various purposes. The amylolytic activity was shown by isolates B. coagulans CAR3, B. licheniformis CAR4, B. megaterium CAR5, Act. pyogenes CAR1, and P. stutzeri CAR8. Esterases and lipases were produced by Coryne. renale CAR 7, Bacillus, Ps. stutzeri, and Corynebacterium. The presence of proteolytic activity was observed in B. circulans CAR 2, B. coagulans CAR3, B. licheniformis CAR4, B. megaterium CAR5, Coryne. renale CAR7, and Corynebacterium.
In another study, Vendan et al. (2010) studied 18 isolates of endophytic bacteria isolated from Ginseng (Panax ginseng C.A. Meyer) medicinal plants. Among these 18 isolates 14 isolates of endophytic bacteria were producing Indole Acetic Acid in nutrient broth. The ability to produce IAA is considered for the development of plant growth. Also, IAA-producing endophytic bacterial screening was studied for the isolates from micropropagated plantlets of Echinacea. These bacteria include Acinetobacter, Bacillus, Pseudomonas, Wautersia (Ralstonia), and Stenotrophomonas. Pseudomonas stutzeri P3 strain which have been extensively exploited for the production of IAA plant growth regulator (Lata et al. 2006).
4.5 Conclusion
The need for new bioactive compounds to overcome the growing problems of drug resistance in microorganisms and the appearance of new diseases is of increasing importance. The capability of fungi to produce bioactive metabolites has encouraged researchers to isolate and screen fungi from diverse habitat and environments to search for novel bioactive metabolites. Therefore, endophytes have been proved as an outstanding source of both novel and bioactive natural products, which have an enormous potential for the development of new drugs and agricultural products. Consequently, endophytes are known to be a rich and reliable source of biologically active compounds with potential benefits in medicinal, industrial, and agricultural application. In contrast, the development of techniques such as combinatorial chemistry and equipment such as peptide synthesizers gives rise to exciting opportunities and expectations for the synthesis of biological active compounds. Additionally, as most endophyte research has been conducted on cultivated species, the diversity of studied endophytes has been further restricted by limitations in the ability to cultivate endophytes in the laboratory.
In spite of the increased number of reports in the last decade, endophytes are still a relatively poorly investigated group of microorganisms. Therefore, the research focusing on endophytes is a promising field in the chemistry and biological properties of natural products. To overcome the infectious disease, there is need for a variety of novel antimicrobial compounds of biological origin. The endophytes hold enormous potential as sources of antimicrobials. These endophytes may open new vistas for the development of new drugs and agricultural products. The multi-drug resistance problem in microbes underscores the need for further research on novel metabolites obtained from endophytes.
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The corresponding author is thankful to DRDO and DBT, New Delhi for partial financial assistance. Mahendra Rai and Aniket Gade thank Department of Environment, Government of India, New Delhi for financial assistance.
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Rathod, D., Dar, M., Gade, A., Shrivastava, R.B., Rai, M., Varma, A. (2013). Microbial Endophytes: Progress and Challenges. In: Chandra, S., LATA, H., Varma, A. (eds) Biotechnology for Medicinal Plants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-29974-2_4
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