[Frontiers in Bioscience E4, 2045-2070, January 1, 2012]
Fungal endophytes: A potential source of antifungal compounds
Sunil Kumar Deshmukh1, Shilpa Amit Verekar1
1
TABLE OF CONTENTS
1. ABSTRACT
The prevalence of invasive fungal infections has increased significantly during organ transplantation, cancer chemotherapy and allogeneic bone marrow transplantation. However, only a limited number of antifungal agents are currently available for the treatment of life-threatening fungal infections. Although new antifungal agents have been introduced in the market, the development of resistance to antifungal drugs has become increasingly apparent, especially in patients with long term treatment. Microbial natural products have always been an alternative natural source for the isolation of novel molecules for various therapeutic applications. Endophytes are the microorganisms that colonize internal tissues of all plant species and represent an abundant and dependable source of bioactive and chemically novel compounds with potential for exploitation in a wide variety of medical, agricultural and industrial arenas. In the present review several metabolites obtained from endophytic fungi with a potential as antifungal agents are mentioned with bioactivity including volatile organic compounds. The compounds reported here with a diverse scaffold can be a potential starting point for new antifungal agents either as such or after chemical modification.
2. INTRODUCTION
The role of fungi as a source of antibiotics was first established by the pioneering work of Sir Alexander Fleming in 1928 leading to the discovery of Penicillin (1), followed by the work of Brotzu who found Cephalosporin C (2, 3). These discoveries are milestones in the discovery of antibacterials from fungi. The discovery of Griseofulvin (4) gave the first antifungal agent of fungal origin. Well known antifungals are Amphotericin B, Nystatin and Cycloheximide but they possess inherent toxicity problems. Antifungal compounds can also be used as agrochemicals to control plant diseases. But such chemicals used as agrochemicals have various health hazard problems. Hence there is a need for naturally occurring compounds which are less toxic, target specific, easily degradable and can compete with synthetic pesticides. The whole area of entomopathogenic fungi as biopesticides has been developed with crop destroying pests in mind, specially Helicoverpa armigera. Compounds like Echinocandin (5), Mulundocandin (6), Papulacandin (7) and Pneumocandin (8) isolated from fungi have been developed as antifungal agents for human fungal infections eg. Caspofungin, Micafungin, Anidulafungin (9-11). These molecules are beta- (1,3)-glucan synthesis inhibitors and have anti-Pneumocystis carinii activity. Pneumocystis carinii infection is now very common in immunocompromised hosts. It is the most common lethal infection in patients with AIDS. Pseudomycins, represent a family of lipopeptides that are active against plant and human pathogenic fungi and are isolated from Pseudomonas syringae, a plant-associated bacterium (12). It can be a candidate molecule for use in human medicine especially after structural modification which can remove mammalian toxicity (13-14). The problem of resistance against these drugs and also against the other existing drugs e.g. azoles (Ketoconazole, Miconazole, Itraconazole, Fluconazole, Voriconazole, Posaconazole etc) still exists (15-16).
Natural products from medicinal plants and microorganisms are the most consistent and productive source for the "first-in-class" drugs (17). Recently, a great deal of interest has been generated by discovery of remarkable pharmacological agents from endophytic fungi (18). There is a whole area of endophytic fungi that has not really been explored or exploited in any great detail.
Endophytes living asymptomatically within plant tissues have been found in almost all plant studied to date (19). They play a major role in physiological activities of host plants influencing enhancement of stress, insect, nematode and disease resistance (20-23). Endophytes can also accelerate plant growth and nitrogen fixing capabilities of host plants (24-25). Endophytes constitute a valuable source of bioactive secondary metabolites (26-29) and would be a source of new drugs of biotechnological importance and plant disease management programs (22, 30-31).
Each of the nearly 300,000 species of land plant on earth is likely to host one or more endophyte species (32). Strobel and Daisy (18) commented that endophytes could be a goldmine of secondary metabolites. Pestalotiopsis sp. can be considerd as "the E. coli of the rain forests" and P. microspora, a "microbial factory" of bioactive secondary metabolites. According to them a variety of chemical structures are seen such as Taxol, Torreyanic acid, Ambuic acid, Cryptocandin, Subglutinol A and B and others.
New organisms and many novel natural products from endophytic fungi inhibit or kill a wide variety of harmful microorganisms like bacteria, fungi, viruses and protozoans that affect humans and animals (33). Endophytes do produce secondary metabolites in culture, but the temperature, composition of the medium and the degree of aeration will affect the amount and kind of compounds produced (34), including steroids, xanthones, phenols, isocoumarins, perylene derivatives, quinines, furandiones, terpenoids, depsipeptides and cytochalasins (33-37).
Here we are covering the metabolites obtained from endophytic fungi, belonging to various classes of fungi along with unidentified fungi and their potential as antifungal agent. Many of these compounds are shown in Table1.
3. ANTIFUNGAL COMPOUNDS PRODUCED BY ENDOPHYTIC FUNGI
3.1. Compounds produced by coelomycetes
The genus Pestalotiopsis exist as an endophyte in most of the world's rainforests and are extremely biochemically diverse. Some examples of products coming from this group of endophtyes are described herein. Ambuic acid (1) (Figure 1) is a highly functionalized cyclohexenone and was isolated from endophytic fungi Pestalotiopsis microspora, P. guepinii and Monochaetia sp. from rainforest plants. It was active against Pythium ultimum with an MIC of 7.5 mcg/ml and also active against several Fusarium sp., Diplodia natelensis and Cephalosporium graminineum but was found inactive against phytopathogenic fungi namely Pyricularia oryzae, Rhizoctonia solani, Botrytis cinerea and human pathogenic fungi suggesting that the role played by this compound in the fungus plant relationship is that of providing protection to the plant by virtue of its antimycotic activity (38-39). Ambuic acid also targets the quorum sensing mediated virulence expression of gram-positive bacteria (40). Pestacin (2) and Isopestacin (3) (Figure 1) were obtained from culture fluids of P. microspora, an endophyte isolated from the combretaceaous tree, Terminalia morobensis. Pestacin and isopestacin display antimycotic as well as antioxidant activities (41- 42).
Another species of Pestalotiopsis namely P. jesteri, an endophytic fungal species isolated from the inner bark of small limbs of a Fragraea bodenii located at the singsing grounds of the Aluakambe village from the Septik river area of Papua New Guinea, produces the highly functionalized cyclohexenone epoxides, Jesterone (4) and Hydroxyjesterone (5) (Figure 1). Jesterone was found active againt Pythium ultimum, Aphanomyces sp., Phytophthora citrophthora, Phytophthora cinnamomi, Sclerotinia sclerotiorum, Rhizoctonia solani, Geotrichum candidum and Pyricularia oryzae with MIC of 25, 6.5, 25, 6.5, 100, 25, >100 and 25 mcg/ml. Hydroxyjesterone was also found active against Aphanomyces sp. and Phytophthora cinnamomi with MIC of 125 and 62.5 mcg/ml (43).
Pestalachloride A-C (6-8) (Figure 1), three new chlorinated benzophenone derivatives were isolated from an endophytic fungus Pestalotiopsis adusta. The fungus was isolated from unidentified tree in Xinglong near Dongzai Hainan Province, Republic of China. These compounds were evaluated for antifungal activity against the plant pathogenic fungi namely Fusarium culmorum, Gibberella zeae and Verticillium aibo-atrum. Pestalachloride A displayed potent antifungal activity against F. culmorum, with an IC50 value of 0.89 micromolar, while Pestalachloride B exhibited remarkable activity against G. zeae, with an IC50 value of 1.1 micromolar whereas Pestalachloride C did not show noticeable in-vitro antifungal activities against F. culmorum, G. zeae and V. aibo-atrum (IC50 > 100 micromolar) (44).
Pestafolide A (9) (Figure 1), a new reduced spiroazaphilone derivative and Pestaphthalide A and B (10-11) (Figure 1), two new isobenzofuranones were isolated from an endophytic fungus Pestalotiopsis foedan. The fungus was isolated from the branch of an unidentified tree near Dongzai, Hainan Province, Republic of China. The isolated compounds were evaluated for antifungal activity against Candida albicans (ATCC 10231), Geotrichum candidum (AS2.498) and Aspergillus fumigatus (ATCC 10894) in agar diffusion assays. Pestafolide A (9) displayed antifungal activity against Aspergillus fumigatus (ATCC 10894), with a zone of inhibition of 10 mm at 100 mcg/disk. Pestaphthalide A (10) showed activity against Candida albicans (ATCC 10231), with 13 mm zone of inhibition and Pestaphthalide B (11) showed activity against Geotrichum candidum (AS2.498) with 11 mm zone of inhibition when tested at the same level (Fluconazole: 18-28mm zones of inhibition for C. albicans, A. fumigatus, and G. candidum at 100 mcg/disk) (45).
Pestalofone A-E (12-16) (Figure 1), five new cyclohexanone derivatives were isolated from Pestalotiopsis fici, isolated from the branches of an unidentified tree in suburb of Hangzhou, Zhejiang Province, Republic of China. Pestalofones A-E were evaluated for activities against Candida albicans (ATCC 10231), Geotrichum candidum (AS2.498) and Aspergillus fumigatus (ATCC 10894). Pestalofone C and E showed significant antifungal activity against A. fumigatus, with IC50 / MIC values of 1.10/35.3 and 0.90/31.2 micromolar, respectively (The positive control Fluconazole showed IC50/MIC values of 7.35/163.4 micromolar) (46).
Phomopsis is another genus which exist as an endophyte associated with most of the plants and are extremely biochemically diverse. Here are some examples of bioactive metabolites products by this endophytic genus. Cytosporone B and C (17-18) (Figure 1) were isolated from an endophytic fungus Phomopsis sp. ZSU-H76 obtained from the stem of mangrove tree Excoecaria agallocha Linn from Dongzai, Hainan, China. Both the compounds were found active against Candida albicans and Fusarium oxysporum with an MIC ranging from 32 to 64 mcg/ml (47). Cytosporone B (17) was also reported from an endophytic fungus, Dothiorella sp., strain HTF3 isolated from mangrove plant Avicennia marina at the estuary of Jiulong River, Fujian Province. It showed activities against fungi namely Aspergillus niger, Trichoderma sp. and Fusarium sp. with MIC of 0.125, 62.5 and 62.5 mcg/ml, respectively (48).
Phomoxanthone A (19) (Figure 1), a dimeric xanthone was isolated from an endophytic fungus Phomopsis sp., isolated from the stem of Costus sp. (Costaceae) growing in the rain forest of Costa Rica. It showed moderate inhibition of Ustilago violacea at a concentration of 10mg/ml. Phomoxanthone A (19) showed strong activity against phytopathogenic fungi namely Phytophthora infestans, Botrytis cinerea, Pyricularia oryzae and Ustilago violacea (49).
Thirteen metabolites viz Phomosine A-G (20-26), 6-hydroxy- 6-isopropylcyclohex-1-enecarboxylic acid (27), (1aS,3R,4R,4aR,6S,7R,8aS)-7-chloro-3,6-dihydroxy-3,4a,8,8-tetramethyl-octahydro-1aH-naphtho (1-b)oxirene-4-carboxylic acid (28), 5-methylmellein (29), 4-hydroxy-5-methylmellein (30), 2-quinazolin-4 (3H)-one (31) and Alternariol (32) (Figure 1) were isolated from the endophytic fungus Phomopsis sp. isolated from Adenocarpus foliolosus from Gomera. The fungicidal properties of these compounds were evaluated against Microbotryum violaceum. Metabolites 20, 22, 26 and 29 exhibited moderate inhibitory activity (50).
Five 10-membered lactones (33-37) (Figure 1) were isolated from Phomopsis sp. YM 311483, obtained from the stem of Azadirachta indica growing in Yuanjiang Country, a tropical region in Yunnan province, People's Republic of China. These lactones were evaluated for their antifungal activity against seven plant pathogens namely Aspergillus niger, Botrytis cinerea, Fusarium avenaceum, F. moniliforme, Helminthosporium maydis, Penicillium islandicum and Ophiostoma minus, using the dose-dependent paper-disk diffusion method. All five compounds showed weak antifungal activities. Compound (36) was the most potent, with MIC values in the range of 31.25-500 mcg/ml, interestingly compound (36) was more active than compound (35), even though their structures differed only in the position of the acetoxy substituent (51).
Phomol (38) (Figure 1), a polyketide lactone was isolated from Phomopsis sp., isolated from medicinal plant Erythrina crista-galli. It exhibited antiinflammatory, weak cytotoxic activity, antibacterial and antifungal activity against both yeast and filamentous fungi (52).
Cerulenin (39) (Figure 1) was isolated from an endophytic fungus Phomopsis sp., isolated from an asymptomatic leaf of a tropical rainforest tree from French Guyana (53). It is an inhibitor of fatty acid and polyketide synthases with known anti-Candida activity (54).
Two new metabolites, Ethyl 2, 4-dihydroxy-5,6-dimethylbenzoate (40) and Phomopsilactone (41) (Figure 1) were isolated from Phomopsis cassiae, an endophytic fungus in Cassia spectabilis. Both the compounds displayed strong antifungal activity against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum and the detection limit for both the compounds was 1 mcg, the same as for the positive control Nystatin (55).
Cycloepoxylactone (42) (Figure 1), was isolated from an endophytic fungus Phomopsis sp. isolated from the leaves of Laurus azorica growing in Gomera, Spain. It exhibited good antifungal activity against Microbotryum violaceum with radius of 10mm at the concentration of 50 mcg/disk (56).
Cadinane sesquiterpenes derivatives namely two diastereoisomers of 3,9,12-trihydroxycalamenenes (43-44), 3,12-dihydroxycalamenene (45), 3,12-dihydroxycadalene (46) and 3,11,12-trihydroxycadalene (47) (Figure 1) were isolated from Phomopis cassiae, isolated from Cassia spectabilis collected from Brazil. The antifungal activity of these compounds was evaluated against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum. The compound 3,11,12-trihydroxycadalene (47) was the most active compound and the detection limit for the compound was found to be 1.0 mcg , comparable with the same amount of the standard Nystatin. The compound 3, 12-dihydroxycadalene (46) also exhibited potent activity against two fungi tested (57).
Phomodione (48) (Figure 1), was isolated from a Phoma sp., an endophyte on a Guinea plant (Saurauia scaberrinae). Phomodione exhibited antifungal activity against Pythium ultimum, Sclerotinia sclerotiorum and Rhizoctonium solani, with MIC between 3 and 8 mcg/ml (58).
Pyrenophorol (49), a known macrolide and (-) dihydropyrenophorin (50), together with four new analogues; 4-acetylpyrenophorol (51), 4-acetyldihydropyrenophorin (52), cis-dihydropyrenophorin (53) and tetrahydropyrenophorin (54) and three novel ring-opened derivatives named seco-dihydropyrenophorin (55), 7-acetyl seco-dihydropyrenophorin (56) and seco-dihydropyrenophorin-1,4-lactone (57) (Figure 1) were isolated from Phoma sp., an endophytic fungus isolated from Lycium intricatum from Gomera, Spain. All the nine compounds exhibited antifungal activity against Microbotryum violaceum (59).
Moriniafungin (58) (Figure 1), a novel sordarin analog with potent antifungal activity was isolated from Morinia longiappendiculata isolated from stems of four plant species namely Santolina rosmarinifolia, Helichrysum stoechas, Thymus mastichina and Calluna vulgarisin collected from central Spain. Moriniafungin exhibited an MIC of 6 mcg/ml against Candida albicans and IC50 ranging from 0.9 to 70 mcg/ml against a panel of clinically relevant strains namely Candida albicans (MY1055), Cryptococcus neoformans (MY 2062), Cr. neoformans (ATCC 66031), Candida glabrata (MY1381), C. parapsilosis (ATCC 22019), C. krusei (ATCC 6258) and C. lusitaniae (MY1396) (60- 61).
Colletotric acid (59) (Figure 1) was isolated from Colletotrichum gloeosporioides, an endophytic fungus colonized inside the stem of Artemisia mongolica and inhibited the growth of the pathogenic fungus Helminthosporium sativum with MIC value of 50 mcg/ml (62).
3beta,5alpha-dihydroxy-6beta-acetoxy-ergosta-7,22-diene (60), 3beta,5alpha-dihydroxy-6beta-phenylacetyloxy-ergosta-7,22-diene (61), 3beta-hydroxy-ergosta-5-ene (62) and 3beta-hydroxy-5alpha,8alpha-epidioxy-ergosta-6,22-diene (63) (Figure 1) were characterized from the culture of Colletotrichum sp., an endophyte isolated from inside the stem of Artemisia annua. These compounds exhibited antifungal activities against Candida albicans and Aspergillus niger (MICs: 50-100 mcg/ml) (63).
Cis-4-hydroxy-6-deoxyscytalone (64) and (4R)-4, 8-dihydroxy-alpha-tetralone (65) (Figure 1) were isolated from endophytic fungus Colletotrichum gloeosporioides residing in healthy leaves of Cryptocarya mandioccana. The antifungal activity of these two compounds was evaluated and the detection limit of these compounds required to inhibit growth of the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum was 5.0 mg, comparable with the positive control Nystatin (64).
Exochromone (66) (Figure 1), a highly substituted chromone dimer was isolated from Exophiala sp. isolated from Adenocarpus foliolosus, growing on the hills of Baranco de Los Jargus, Gomera. Exochromone showed a radial zone of inhibition of 9 mm at the concentration of 1mg/ml against Microbotryum violaceum (65).
3.2. Compounds produced by ascomycetes
Cryptocandin A (67) (Figure 2), an antifungal lipopeptide was isolated and characterized from the endophytic fungus, Cryptosporiopsis quercina isolated from stem of Tripterigeum wilfordii (66). This compound contains a number of unusual hydroxylated amino acids and a novel amino acid, 3- hydroxy-4-hydroxymethylproline and a beta- (1,3)-glucan synthesis inhibitor. Cryptocandin A is active against some important human fungal pathogens including Candida albicans and Trichophyton sp. and also against a number of plant pathogenic fungi, including Sclerotinia sclerotiorum and Botrytis cinerea. Similarly a group of peptides, Echinocandin A, B, D and H (68-71) (Figure 2), also a beta- (1,3)-glucan synthesis inhibitors were isolated from endophytic Cryptosporiopsis sp. and Pezicula sp. in Pinus sylvestris and Fagus sylvatica and showed to be antifungal (67). Cryptocin (72) (Figure 2), a tetramic acid is an antifungal compound also obtained from Cryptosporiopsis cf quercina isolated from the inner bark of the stem of Tripterigeum wilfordii. This unusual compound possesses potent activity against Pyricularia oryzae, with MICs of 0.39 mcg/ml, a causal agent of rice blast disease, as well as a number of other plant pathogenic fungi (68).
Enfumafungin (73) (Figure 2), a triterpenoid glucoside was produced by Hormonema sp. (ATCC 74360) an endophytic fungus isolated from Juniperus communis. Enfumafungin shows interesting antifungal spectrum and its effect on the morphology of Aspergillus fumigatus was shown to be comparable to that of the glucan synthase inhibitor, Pneumocandin B (69).
Epichlicin (74) (Figure 2), a novel cyclic peptide was isolated from Epichloe typhina, an endophytic fungus from Phleum pratense. Epichlicin showed inhibitory activity toward the spore germination of Cladosporium phlei, a pathogenic fungus of Epichloe typhina plant at an IC50 value of 22 nanomolars (70).
New naphthoquinone spiroketals, namely Preussomerin EG1-EG3 (75-77) (Figure 2), were isolated from the mycelium of Edenia gomezpompae, isolated from the leaves of Callicarpa acuminata (Verbenaceae) collected from the ecological reserve El Eden, Quintana Roo, Mexico. The new spiroketals displayed significant growth inhibition against all the phytopathogens namely Phytophthora capsici, P. parasitica, Fusarium oxysporum and F. solani with IC50 values in the range of 20 to 170 mcg/ml (71).
Weber et al (53) reported 5- (1,3-Butadien-1-yl)-3- (propen-1-yl)-2 (5H)-furanone (78) (Figure 2) from an endophytic strain E99297, isolated from the twig of Cistus salvifolius, which was previously shown by Kopcke et al (72) to belong to the Sarcosomataceae (order Pezizales). The compound was isolated on the basis of its anti-Candida activity and was identical to 5- (E)-buta-1,3-dienyl-3 (E)-propenyl-5Hfuran-2-one isolated by Kopcke et al (72).
Depsidones, Botryorhodine A-D (79-82) (Figure 2) were produced by Botryosphaeria rhodina isolated from the stems of the medicinal plant Bidens pilosa (Asteraceae). Botryorhodine A exihibited an MIC of 26.03 and 191.60 micromolar against Aspergillus terreus and Fusarium oxysporum respectively, whereas the compound botryorhodine B exihibited an MIC of 49.70 and 238.80 micromolar against Aspergillus terreus and Fusarium oxysporum, respectively (73).
Dinemasone A-C (83-85), (Figure 2) were isolated from Dinemasporium strigosum, isolated from the roots of Calystegia sepium from the shores of Baltic Sea, Wustrow, Germany. The dinemasone A and B exhibited considerable activity against Microbotryum violaceum (74).
Chaetoglobosin A and C (86- 87) (Figure 2), were characterized from an endophytic Chaetomium globosum isolated from the leaves of Ginkgo biloba. Both the compounds displayed marked inhibitory activity against Mucor miehei by agar diffusion method with the zone of inhibition of 25 and 15 mm in diameter at 10 mcg/disk respectively (75).
Sordaricin (88) (Figure 2), a known antifungal metabolite, was isolated from an endophytic fungus Xylaria sp. PSU-D14, isolated from the leaves of Garcinia dulcis, collected in Songkhla Province, Thailand. It exhibited moderate antifungal activity against Candida albicans ATCC 90028 with a MIC value of 32 mcg/ml (76).
Griseofulvin (89) and 7-dechlorogriseofulvin (90) (Figure 2) were isolated from Xylaria sp. F0010 isolated from Abies holophylla. Compared to 7-dechlorogriseofulvin, griseofulvin showed high in-vivo and in-vitro antifungal activity and effectively controlled the development of plant pathogenic fungi namely Magnaporthe grisea, Corticium sasakii, Puccinia recondita and Blumeria graminis f. sp. hordei at doses of 50 to 150 mcg/ml, depending on the disease (77). Griseofulvin (89) (Figure 2) was also isolated from an endophytic fungus PSU-N24 isolated from Garcinia nigrolineata. It displayed strong antifungal activity against Microsporum gypseum SH-MU-4 with a MIC value of 2 mcg/ml (78).
2-hexyl-3-methyl-butanodioic acid (91) and Cytochalasin D (92) (Figure 2) were isolated from an endophytic fungus Xylaria sp. isolated from Palicourea marcgravii. These compounds were found active against phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum (79).
7-amino-4-methylcoumarin (93) (Figure 2) was isolated from an endophytic Xylaria sp., obtained from Ginkgo biloba L. The compound showed strong in-vitro antifungal activities with MIC of 15, 40, and 25 mcg/ml against Candida albicans, Penicillium expansum and Aspergillus niger respectively (80).
3.3. Compounds produced by hyphomycetes
A new pyrone derivative, Penicillone (94), together with Pyrenocine A and B (95-96) (Figure 3), were isolated from the endophytic fungus Penicillium paxilli PSU-A71, isolated from the leaves of Garcinia atroviridis, collected in Songkhla Province, Thailand. All the compounds were tested for antifungal activity against Microsporum gypseum SH-MU-4. Pyrenocine B (96) showed mild activity with a MIC value of 32 mcg/ml while penicillone (94) and pyrenocine A (95) were much less active than pyrenocine B (96) with MIC values of 64 and 128 mcg/ml, respectively (81).
2,6-dihydroxy-2-methyl-7-(prop-1E-enyl)-1-benzofuran-3 (2H)-one (97), Massariphenone (98) and Ergosterol peroxide (99) (Figure 3) were reported from Verticillium sp. isolated from roots of wild Rehmannia glutinosa from Wushe County, Henan Province, People's Republic of China. Minimum morphological deformation concentration (MMDC) of compounds (97-99) towards Pyricularia oryzae P-2b was 1.95, 125.0 and 7.8 mcg/ml respectively. Compound (97) exhibited the strongest antibiotic activity but compound (98) only slightly inhibited growth of Septoria sp. and Fusarium sp. Compounds (97) and (99) clearly inhibited biomass accumulations at a low concentration (0.97 mcg/ml) in liquid culture. Growth of the Verticillium sp. itself was also inhibited to some degree by compounds (97) and (99). Compound (97) showed selective inhibition and inhibited pathogens more strongly; in contrast compound (99) displayed no selectivity (82).
Arthrichitin (100) (Figure 3), a cyclic depsipeptide was isolated from Arthrinium phaeospermum obtained from unidentified grass (83). It was also isolated as LL15G256γ from the marine fungus Hypoxylon oceanicum (84-85). Arthrichitin has a broad-spectrum of activity against Candida sp., Trichophyton sp. and several phytopathogens. In-vitro testing has shown that arthrichitin inhibits membrane preparations of fungal chitin and glucan synthases, with a greater potency against chitin synthase. Fungal cells exposed to arthrichitin undergo morphological changes similar to the effects of chitin synthase inhibitor, Polyoxin B (83). The morphological effects of arthrichitin occur at concentrations that are tenfold below those required to inhibit chitin synthase. This suggests the existence of another target for arthrichitin, possibly an isozyme of chitin synthase not present in the membrane preparation (86). It is also possible that the compound alters regulatory processes in the cell cycle that affect the cell wall. The in-vitro potency of arthrichitin is too low for its use in the clinic. However, it has been suggested that the development of analogs, such as those based on the much larger cyclic peptides, the echinocandins, might yield congeners with improved activity (86).
The solanapyrone analogues, Solanapyrone C, N and O (101-103), Nigrosporalactone (104) and Phomalactone (105) (Figure 3) were isolated from Nigrospora sp. YB-141, an endophytic fungus isolated from Azadirachta indica. All the compounds were tested for their antifungal properties against seven phytopathogenic fungal strains namely Aspergillus niger, Botrytis cinerea, Fusarium avenaceum, Fusarium moniliforme, Helminthosporium maydis, Ophiostoma minus and Penicillium islandicum. All five compounds showed antifungal activities against B. cinerea with MIC values in the range of 31.25-250 mcg /ml (87).
Trichodermin (106) (Figure 3) was characterized from Trichoderma harzianum, an endophytic fungus from Llex cornuta. Plant experimental results showed that trichodermin exhibited significant protective effect to early blight on tomato and damping-off on cucumber. The EC50 values of trichodermin inhibiting the mycelia growth of Alternaria solani and Rhizoctonia solani were 3.35 and 3.59mg/L, respectively. In addition, protective and therapeutic effects of trichodermin at 100 mg/L against A. solani and R. solani were 97.8%, 98.1% and 96.7%, 97.3%, respectively (88).
Nodulisporins D-F (107-109), (3S,4S,5R)- 2,4,6-trimethyloct-6-ene-3,5-diol (110), 5-hydroxy-2-hydroxymethyl-4H-chromen-4-one (111), 3- (2,3-dihydroxyphenoxy)-butanoic acid (112) and Benzene-1,2,3-triol (113) (Figure 3) were isolated from Nodulisporium sp. an endophytic fungus, isolated from the plant Erica arborea from Gomera. These compounds were found active against Microbotryum violaceum (89).
Wang et al (90) isolated Brefeldin A (114) (Figure 3), with a wide range of biological activities, namely antifungal, antiviral, antimitotic, antiinflammatory and antitumor (91-95) from Aspergillus clavatus and Paecilomyces sp. endophytic in Chinese Taxus mairei and Torreya grandis. Brefeldin A was also isolated from an endophytic fungal strain of Eupenicillium brefeldianum, isolated from a Chinese traditional medicinal plant Arisaema erubescens (96) and from an endophytic fungal strain of Cladosporium sp, isolated from a Chinese traditional medicinal plant Quercus variabilis (97).
CR377 (115) (Figure 3), a new pentaketide was isolated from fungus CR377 (Fusarium sp.) isolated from the interior of a surface-sterilized pieces of Selaginella pallescens stem tissue, collected in the Guanacaste Conservation Area of Costa Rica. CR377 was tested against Wisconsin and 109 strain of Candida albicans by agar diffusion method. The compound exhibited inhibition zones of 20 and 24 mm against both Candida albicans strains: Wisconsin and 109 respectively. Nystatin, a positive control produced inhibition zones of 19 and 22 mm against the Wisconsin and 109 strains respectively at the concentration of 100 units (approximately 30mcg) (98).
Four known naphtho-gamma-pyrones, Rubrofusarin B (116), Fonsecinone A (117), Asperpyrone B (118) and Aurasperone A (119) (Figure 3) were isolated from Aspergillus niger IFB-E003, an endophyte isolated from leaves of Cynodon dactylon collected from Yancheng Biosphere reserve, People's Republic of China. These compounds exhibited growth inhibition against Trichophyton rubrum and Candida albicans with MICs ranging between 1.9 to 15.6 mcg/ml (99).
Four natural nitro metabolites, 1-hydroxy-5-methoxy-2-nitro-naphthalene (120), 1,5-dimethoxy-4-nitronaphthalene (121), 1-hydroxy-5-methoxy-2,4-dinitronaphthalene (122) and 1,5-di-methoxy-4,8-dinitronaphthalene (123) known from chemical synthesis but new as natural products, were isolated together with 1-hydroxy-5-methoxynaphthalene (124) (Figure 3) from an endophytic fungus, Coniothyrium sp. isolated from the shrub Sideritis chamaedryfolia, from an arid habitat near Alicante, Spain. Compounds (120-122) and (124) showed excellent activity against Microbotryum violaceum (100).
Fusicoccane diterpenes, named Periconicin A and B (125-126) (Figure 3) with antibacterial activities were isolated from an endophytic fungus Periconia sp., OBW-15, collected from small branches of Taxus cuspidate (101). Periconicin A (125) showed potent inhibitory activity against the agents of human mycoses, including Candida albicans, Trichophyton mentagrophytes and T. rubrum, with MIC in the range of 3.12-6.25 mcg/ml (102).
3-hydroxy-1- (2,6-dihydroxyphenyl)butan-1-one (127), 1- (2,6-dihydroxyphenyl)butan-1-one (128), 1- (2-hydroxy-6-methoxyphenyl)butan-1-one (129), 5-hydroxy-2-methyl-4H-chromen-4-one (130), 2,3-dihydro-5-hydroxy-2-methylchromen-4-one (131), 2,3-dihydro-5-methoxy-2-methylchromen-4-one (132), 8-methoxynaphthalen-1-ol (133), 1,8-dimethoxynaphthalene (134), Nodulisporin A (135), Nodulisporin B (136), Daldinol (137), Nodulisporin C (138) and (4E,6E)-2,4,6-trimethylocta-4,6-dien-3-one (139) (Figure 3) were isolated from Nodulisporium sp. from Juniperus cedre from Gomera Island. Compounds (127-139) were tested at the concentration of 0.25 mg/filter disc for antifungal activity. Compounds (128-139) showed activity against Microbotryum violaceum while compounds (128), (130), (132), (134) and (139) showed activity against Septoria tritici (103).
Monomethylsulochrin (140), Rhizoctonic acid (141), Asperfumoid (142), Physcion (143), 7,8-dimethyl-iso-alloxazine (144) and 3,5-dichloro-p-anisic acid (145) (Figure 3) were identified from Penicillium sp. isolated from the leaf of Hopea hainanensis. All of the six isolated compounds were subjected to antifungal activity against three human pathogenic fungi namely Candida albicans, Trichophyton rubrum and Aspergillus niger. Compounds (141-143) and (145) inhibited the growth of C. albicans with MICs of 40.0, 20.0, 50.0 and 15.0 mcg/ml, respectively and compound (145) showed growth inhibition against A. niger with MICs of 40.0 mcg/ml (104).
Benzopyran derivatives, 2-methyl-5-methoxy-benzopyran-4-one (146) and (2'S) 2- (propan-2'-ol)-5-hydroxy-benzopyran-4-one (147) (Figure 3) were isolated from Curvularia sp. obtained from the leaves of Ocotea corymbosa, a native plant of the Brazilian Cerrado. Compound (146) and (147) showed weak in-vitro antifungal activity against Cladosporium sphaerospermum and C. cladosporioides, showing detection limit of 10 mcg for both substances. Nystatin was used as a positive control showing a detection limit of 1mcg (105).
The antifungal metabolites, named Asperfumoid (142), Physcion (143), Fumigaclavine C (148), Fumitremorgin C (149) and Helvolic acid (150) (Figure 3) were obtained from an endophytic fungus, Aspergillus fumigatus CY018 isolated from the leaf of Cynodon dactylon. Compounds (142, 143, 148-150) inhibited the growth of Candida albicans with MICs of 75.0, 125.0, 31.5, 62.5, and 31.5 mcg/ml, respectively. The MIC of ketonazole used as a positive reference against C. albicans was 31.5 mcg /ml respectively (106).
Aspergillus clavatonanicus, an endophytic fungal strain from Taxus mairei yielded Clavatol (151) and Patulin (152) (Figure 3). Both compounds exhibited in-vitro inhibitory activity against several plant pathogenic fungi, namely Botrytis cinerea, Didymella bryoniae, Fusarium oxysporum f. sp. cucumerinum, Rhizoctonia solani and Pythium ultimum (107).
Asperamide A and B (153-154) (Figure 3), a sphingolipid and their corresponding glycosphingolipid possessing a hitherto unreported 9-methyl-C20-sphingosine moiety, were characterized from Aspergillus niger EN-13, an endophytic fungus isolated from marine brown alga Colpomenia sinuosa along the Qingdao coastline of Shandong Province, People's Republic of China. Asperamide A (153) displayed moderate activity against Candida albicans with a zone of inhibition of 20mm (108). A new naphthoquinoneimine derivative namely, 5, 7-dihydroxy-2-(1-(4-methoxy-6-oxo-6H-pyran-2-yl)-2-phenylethylamino)- (1,4) naphthoquinone (155) (Figure 3) was also reported from Aspergillus niger EN-13 isolated from the inner tissue of the marine brown alga Colpomenia sinuosa. It displayed moderate antifungal activity against Candida albicans with an inhibitory zone (10 mm) at 20 mg/well (6 mm) (109).
Isocoumarin derivatives, (12R)-12-hydroxymonocerin (156), (12S)-12-hydroxymonocerin (157), (3R,4R,10R)-4 (2-4) (158) and Monocerin (159) (Figure 3) were isolated from Microdochium bolleyi, an endophytic fungus from Fagonia cretica, from the semiarid coastal regions of Gomera. Compounds (157), (158) and (159) exhibited good antifungal activity while compound (156) exhibited moderate antifungal activities against Microbotryum violaceum (110).
A new diphenyl ether, Neoplaether (160) (Figure 3) was isolated from the culture of Neoplaconema napellum IFB-E016, an endophytic fungus residing in the healthy leaves of Hopea hainanensis from Hainan Island, People's Republic of China. In-vitro antifungal activity of Neoplaether was examined, using Aspergillus niger, Candida albicans and Trichophyton rubrum as test organisms, and it showed obvious activity against C. albicans with an MIC value of 6.2 mcg/ml (that of Amphotericin co-assayed as positive control was 1.5 mcg/ml), whereas no growth inhibition to A. niger and T. rubrum could be discerned when it was tested at 100 mcg/ml (111).
Isofusidienol A-D (161-164) (Figure 3), were produced by Chalara sp. (strain 6661), an endophytic fungus isolated from Artemisia vulgaris. All the isofusidienol compounds exhibited antifungal activity against Candida albicans (112).
Blennolide A-G (165 - 171), seven unusual chromanones, were isolated together with Secalonic acid B (172) (Figure 3) from Blennoria sp., an endophytic fungus from a succulent Carpobrotus edulis growing on Gomera, in the Canary Islands. All the compounds showed strong antifungal activity against Microbotryum violaceum (113).
6,8-Dimethoxy-3- (2'-oxo-propyl)-coumarin (173) and 2,4-dihydroxy-6- ( (1'E,3'E)-penta-1', 3'-dienyl)-benzaldehyde (174) (Figure 3), in addition to a known compound Periconicin B (126), were isolated from Periconia atropurpurea, obtained from the leaves of Xylopia aromatica, a native plant of the Brazilian Cerrado. These compounds were evaluated against Cladosporium sphaerospermum and C. cladosporioides. Only compound (174) exhibited strong antifungal activity against both fungi, showing detection limit of 1.0 mcg, comparable to nystatin (used as a positive control). Compound (173) did not show any antifungal activity and compound (126) showed a relatively weak detection limit of 25.0 mcg (114).
3.4. Compounds produced by unidentified fungus
Cabello et al (115) reported a novel acidic steroid Arundifungin (175) (Figure 4), a beta- (1,3)-glucan synthesis inhibitor from F-042,833, isolated from twig of Olea europea var europea an undetermined coelomycetes and F054,289 a sterile mycelium from leaves of Quercu silex isolated from Ontigola, Madrid, Spain. Arundifungin cause the same pattern of hallmark morphological alteration in Aspergillus fumigatus hyphae as echinocandins, which supports the idea that arundifungin, belongs to the class of glucan synthesis inhibitors. It exhibits antifungal activity against a range Candida sp. with MIC over 2-8 mcg/ml, whereas it is only 1mg/ml for Aspergillus fumigatus.
Khafrefungin (176) (Figure 4) was isolated from an unidentified sterile fungus (MF 6020) cultured from a Costa Rican plant sample. It inhibits fungal sphingolipid synthesis, at the step in which phosphoinositol are transferred to ceramide, resulting in accumulation of ceramide and loss of all of the complex sphingolipids. In-vitro, khafrefungin inhibits the inositol phosphoceramide synthase of Candida albicans with an IC50 of 0.6 nanomolar. Khafrefungin inhibited the growth of Candida albicans, Cryptococcus neoformans and Saccharomyces cerevisiae in liquid culture with MIC of 2, 2 and 15.6 mcg/ml respectively. Khafrefungin does not inhibit the synthesis of mammalian sphingolipids thus making this the first reported compound that is specific for the fungal pathway (116).
Ascosteroside A and B (177-178) (Figure 4) were isolated from E99291, an endophyte from shoots of Cistus salvifolius. Both the compounds showed antifungal activity against a wide range of saprophytic, plant and human pathogenic fungi (53). Ascosteroside A was originally isolated from Ascotricha amphitricha as a metabolite with anti-Candida activity (117), which is now known to be due to inhibition of beta- (1,3)-glucan synthesis (118).
Sphaeropsidin A (179) (Figure 4) was isolated from E99204, an endophyte from an asymptomatic leaf of Quercus ilex and exhibited antifungal activity against yeast and filamentous fungi (53). Sphaeropsidins are a group of pimarane diterpenes known from the anamorphic fungi Sphaeropsis sapinea f. sp. cupressi and Diplodia mutila (119 -120).
6,8-diacetoxy-3,5-dimethylisocoumarin (180), 3-Acetyl-6-hydroxy-4-methyl-2,3 dihydrobenzofuran (181) (Figure 4), were isolated from mycelia sterila, an endophytic fungus from the Canadian thistle Cirsium arvense growing in Lower Saxony, Germany. The compounds were tested against three fungal test organisms namely Mycotypha microspora, Eurotium repens and Ustilago violacae. Compound (180) showed moderate antifungal activity against all tested fungi where as compound (181) was moderately antifungal against Eurotium repens (121).
Pyrenocine A (95), Pyrenocine F-H (182-184) (Figure 4), were isolated from an unidentified endophytic fungus (6760) isolated from Trifolium dubium from Wustrow near the Baltic Sea. Pyrenocine A (95) and G (183) exhibited considerable activity against Microbotryum violaceum (122).
4. VOLATILE ORGANIC COMPOUNDS FROM FUNGUS
Strobel et al (123) reported at least 28 volatile organic compounds (VOC) from xylariaceaous endophytic fungus Muscodor albus (isolate 620), isolated from small limbs of Cinnamomum zeylanicum located in the Lancetilla Botanical Garden near La Ceiba, Honduras which posses antimicrobial properties. These VOC's are a mixture of gases of five classes consisting primarily of various alcohols, acids, esters, ketones and lipids. The most effective class was the esters, of which 1-butanol, 3-methyl-acetate was the most active biologically. The VOC effectively inhibited and killed certain fungi and bacteria, within a period of 1 to 3days. Most test organisms were completely inhibited, and in fact killed namely Pythium ultimum, Phytophthora cinnamomi, Rhizoctonia solani, Ustilago hordei, Stagnospora nodorum, Sclerotinia sclerotiorum, Aspergillus fumigatus, Verticillum dahliae, Tapesia yallundae, Candida albicans, Escherichia coli, Staphylococcus aureus, Micrococcus luteus, Bacillus subtilis. However the growth of Fusarium solani and Cercospora beticola, were only partially inhibited. The antibiotic effect of the VOC's of M. albus is strictly related to the synergistic activity of the compounds in the gas phase. The volatiles of M. albus did not kill M. albus itself or its close relative Xylaria sp., although they did inhibit the growth of Xylaria sp. Other species of Muscodor is Muscodor roseus, an endophyte from small limbs of a fern-leafed (Grevillea pteridifolia) in the Northern Territory of Australia and is also known to produce similar type of VOC's (124).
Recently another species of Muscodor namely Muscodor crispans, isolated from Ananas ananassoides (wild pineapple) growing in the Bolivian Amazon Basin produces VOC's; namely propanoic acid, 2-methyl-, methyl ester; propanoic acid, 2-methyl-; 1-butanol, 3-methyl-;1-butanol, 3-methyl-, acetate; propanoic acid, 2-methyl-, 2-methylbutyl ester; and ethanol. The VOC's of this fungus was effective against a wide range of plant pathogens, namely Pythium ultimum, Phytophthora cinnamomi, Sclerotinia sclerotiorum and Mycosphaerella fijiensis (the black sigatoka pathogen of bananas), and the serious bacterial pathogen of citrus, Xanthomonas axonopodis pv. citri. The VOC's of M. crispans killed several human pathogens, including Yersinia pestis, Mycobacterium tuberculosis and Staphylococcus aureus. Muscodor crispans is only effective against the vegetative cells of Bacillus anthracis, but not against the spores. Artificial mixtures of the fungal VOC's were both inhibitory and lethal to a number of human and plant pathogens, including three drug-resistant strains of Mycobacterium tuberculosis (125).
The mechanism of action of the VOC's of Muscodor spp. on target fungi and bacteria is unknown. A microarray study of the transcriptional response analysis of Bacillus subtilis cells exposed to M. albus VOC's showed that the expression of genes involved in DNA repair and replication increased, suggesting that VOC's are inducing some type of DNA damage in cells, possibly through the effects of one of the naphthalene derivatives (125).
The VOC's of M. albus kill many of the pathogens that affect plants, people and even buildings (123, 126). The term "mycofumigation" has been applied to the practical aspects of this fungus. The first practical demonstration of its effects against a pathogen was the mycofumigation of covered smut infected barley seeds for a few days resulting in 100% disease control (123). This technology is currently being developed for the treatment of fruits in storage and transit (127). Soil treatments have also been effectively used in both field and green house situations (128-130). In these cases, soils are pretreated with a M. albus formulation in order to preclude the development of infected seedlings.
5. OUTLOOK
From the extensive data quoted in this paper by the authors on antifungals and earlier numerous publications on a wide variety of bioactive compounds such as anticancer to name just one, it becomes obvious that endophytes are a feasible source for the discovery of novel molecules yet there are so much more to be discovered. Initially endophyte was an area of interest for the botanists, but after the discovery of interesting bio-active molecules it opened the field to structural chemists and biochemists. The interdisciplinary approach, wherein the knowledge of the botanist is combined with the technology and structural tools of the chemist can lead to real success in this area.
The tropical and sub-tropical rain forests have been used for the isolation of endophytes with an assumption that, the conditions prevailing in these ecosystems would require plants to be armed with antifungal and antibacterial allies. Other possible fruitful areas might include endophytes from plants growing in high alpine regions, desert areas, mangroves, marine weeds etc. as they are struggling to survive in harsh conditions.
Historically it has been assumed that the active ingredients are synthesized by the plant itself, but the discovery that microbial endophytes are capable of synthesizing bio-active compounds has opened up a whole new area of research. Plants used by indigenous people for medicinal purposes and that are endemic to a particular area may be a good source for endophyte isolation (18). A medicinal plant may be growing in the different part of the world and is used in different treatments by different indigenous groups. The endophytes from the same medicinal plant should be investigated from different part of the world for bioactive metabolites and correlated with the activity (131).
The distribution of endophytes within a plant host needs to be studied as some are ubiquitous to all parts of the host, whereas others are found in the roots or roots and stem only, in the stem and leaves only, or only in the leaves. The distribution study will put a light on whether the medicinal property of a particular plant part is plant character or is it because of a specific endophyte residing in that plant part (131).
While studying the endophytic fungi from a particular plant or a group of plants the taxonomic identification is must, which actually should be mandatory for publication or documentation purpose. This will help in correlating the metabolites of host plant and the metabolites of endophytes harboring the same plant.
Not all endophytes are culturable (132), therefore, apart from isolating culturable endophytes from different taxonomic groups of plants and plants growing in different habitats, shotgun metagenomics for endophyte community analysis and function-based screening of their metagenomic libraries could be used to harness the unculturable and truly cryptic endophytes from environmental samples for bioactive metabolites (133).
Endophytic fungal species should be screened for their secondary metabolite spectrum under different growth conditions; culture parameters such as composition of growth medium, aeration, pH and the presence of certain enzyme inhibitors that can change dramatically the secondary metabolite profile and even induce the synthesis of several new metabolites (134).
The review of the literature indicates that novel chemotypes directed against the pathogenic fungi have come from the endophytic microbial source. It is well known that resistance development in pathogens has become a major hazard, for example azole resistant Candida albicans and effective molecules against such multidrug resistant microbes have not been easy to find. The mode of action of majority of compounds reported in this review is not known. The mode of action based screening offers a great scope for the isolation of novel antifungal lead from endophytic fungi. There are compounds like Cryptocandin, Echinocandin A, B, D, H, Sordaricin, Arundifungin, Khafrefungin which are isolated from endophytes and working through specific mode of action and can be a drugable candidate after chemical modification. For example, Echinocandin B was initially isolated from soil fungi; later from an endophytic fungi, and developed as antifungal drug, Anidulafungin by Vicuron Pharmaceuticals (VER002, LY-303366) (135).
There is a great need of culture collection for this group of fungi with trained mycologists having classical and molecular background. The collection will help not only in getting novel secondary metabolites for various pharmaceutical and agricultural applications but also for applications like biotransformation, enzyme production etc to name few.
5. ACKNOWLEDGMENTS
The authors are grateful to Dr Somesh Sharma, MD, Dr. H. Sivaramakrishnan, President, Piramal Life Sciences, Mumbai and Dr. B. N. Ganguli Agharkar Chair Professor, Agharkar Research Institute, Pune, India for all kinds of support during the work.
6. REFERENCES
1. E Chain, H W Florey, A D Gardner, N G Heatley, M A Jennings, J Orr-Ewing, A G Sanders: Penicillin as a chemotherapeutic agent. Lancet 239, 226 - 228 (1940)
doi:10.1016/S0140-6736(01)08728-1
2. G Brotzu: Ricerche su di un nuovo antibiotico. Lavori dell�Istituto d'Igiene di Cagliari 4-18 (1948)
3. E P Abraham, G G F Newton: The structure of cephalosporin C. Biochemical Journal 79, 377-393 (1961)
4. A E Oxford, H Raistrick, P Simonart: Studies on the biochemistry of microorganisms Griseofulvin, C17H17O6Cl, a metabolic product of Penicillium griseofulvum Dierckx. Biochemical Journal 33, 240 (1939)
5. F Benz, F Knusel, J Nuesch, H Treichler, W Voser, R Nyfeler, W Keller-Schierlein: Stoffwechselprodukte von Mikroorganismen. Echinocandin B, einneuartiges Polypeptid Antibioticum aus Aspergillus nidulans var echinulatus. Isolierung und Bausteine. Hel Chem Acta 57, 2459 - 2477 (1974)
doi:10.1002/hlca.19740570818
6. K. Roy, T. Mukhopadhyay, G. C. S. Reddy, K. R. Desikan, B. N. Ganguli: Mulundocandin, A new lipopeptide antibiotic I Taxonomy, Fermentation Isolation and Characterization. J Antibiot 40, 275-280 (1987)
7. A Traxler, J Gruner, J A L Auden: Papulacandins, a new family of antibiotics with antifungal activity I Fermentation, isolation, chemical and biological characterization of papulacandins A, B, C, D, and E. J Antibiot 30, 289-296 (1977)
8. R E Schwartz, R A Giacobbe, J A Bland, R L Monaghan: L671, 329, a new antifungal agent I Fermentation and isolations. J Antibiot 42, 163-167 (1989)
9. D W Denning: Echinocandin antifungal drugs. Lancet 362, 1142-1151 (2003)
doi:10.1016/S0140-6736(03)14472-8
10. N A Kartsonis, J Nielsen, C M Douglas: Caspofungin: the first in a new class of antifungal agents. Drug Resist Updat 6, 197-218 (2003)
doi:10.1016/S1368-7646(03)00064-5
11. N P Wiederhold, R E Lewis: The echinocandin antifungals: an overview of the pharmacology, spectrum and clinical efficacy. Expert Opin Invest Drugs 12, 1313-1333 (2003)
doi:10.1517/13543784.12.8.1313
12. L Harrison, D B Teplow, M Rinaldi, G Strobel: Pseudomycins, a family of novel peptides from Pseudomonas syringae possessing broad-spectrum antifungal activity. J Gen Microbiol 137 (12), 2857-1265 (1991)
doi:10.1099/00221287-137-12-2857
13. Y Z Zhang, X Sun, D J Zeckner, R K Sachs, W L Current, J Gidda, M Rodriguez, S H Chen : Synthesis and anti- fungal activities of 3-amido bearing pseudomycin analogs. Bioorg Med Chem Lett 11, 903-907. (2001)
doi:10.1016/S0960-894X(01)00101-9
14. S H Chen, M Rodriguez: Antifungal lipopeptides: A tale of pseudomycin prodrugs and analogues. Drugs Future 28 (5), 441 (2003)
doi:10.1358/dof.2003.028.05.737309
15. D S Perlin: Resistance to echinocandin-class antifungal drugs. Drug Resist Updates 10, 121-130 (2007)
doi:10.1016/j.drup.2007.04.002
16. M C Arendrup, E Mavridou, K L Mortensen, E Snelders, N Frimodt-Møller, H Khan, W J G Melchers, P E Verweij : Development of Azole Resistance in Aspergillus fumigatus during Azole Therapy Associated with Change in Virulence. PLoS ONE 5 (4), e10080 (2007)
doi:10.1371/journal.pone.0010080
17. D J Newman, G M Cragg: Natural products as sources of new drugs over the last 25 years. J Nat Prod 70 (3), 461-477 (2007)
doi:10.1021/np068054v
18. G A Strobel, B Daisy: Bioprospecting for microbial endophytes and their natural products. Microbiol Mol Bio Rev 67, 491-502 (2003)
doi:10.1128/MMBR.67.4.491-502.2003
19. B Schulz, U Wanke, S Draeger: Endophytes from herbaceous and shrubs: effectiveness of surface sterilization methods. Mycol Res 97, 1447-1450 (1993)
doi:10.1016/S0953-7562(09)80215-3
20. G Carroll: Fungal endophytes in stems and leaves: from latent pathogens to mutualistic symbionts. Ecology 69, 2-9 (1988)
doi:10.2307/1943154
21. J Hallmann, R A Sikora: Toxicity of fungal endophytic secondary metabolites to plant parasitic nematodes and soil borne plant pathogenic fungi. Eur J Plant Pathol 102, 155-162 (1996)
doi:10.1007/BF01877102
22. J L Azevedo, W Macchroni, J O Pereira, W L Araujo: Endophytic microorganisms: are view on insectcontrol and recent advances on tropical plants. Biotechnology 3, 40-65 (2000)
23. A V Sturz, J Nowak: An endophytic community of rhizobacteria and the strategies requires to create yield enhancing associations with crops. Appl Soil Ecol 15, 183-190 (2000)
doi:10.1016/S0929-1393(00)00094-9
24. S C Verma, J K Ladha, A K Tripathi: Evaluation of plant growth promoting and colonization ability of endophytic diazotrophs from deepwater rice. J Biotechnol 91, 127-141 (2001)
doi:10.1016/S0168-1656(01)00333-9
25. M H Rahman, S Saiga: Endophytic fungi (Neotyphodium coenophialum) affect the growth and mineral uptake, transport and efficiency ratiosintallfescue (Festuca arundinacea). Plant Soil 272, 163-171 (2005)
doi:10.1007/s11104-004-4682-6
26. G A Strobel: Rainforest endophytes and bioactive products. Crit Rev Biotechnol 22, 325-333 (2002)
doi:10.1080/07388550290789531
27. V C Verma, R N Kharwar, G A Strobel: Chemical and functional diversity of natural products from plant associated endophytic fungi. Nat Prod Commun 4 (11), 1511-1532 (2009)
28. S K Deshmukh, S A Verekar: Fungal Endophytes: A Potential Source of Anticancer Compounds In: Novel Therapeutic Agents from Plants: Progress and Future Perspectives. Eds. M C Carpinella, M K Rai. Science Publishers, Inc Enfield USA. 175-206 (2009)
doi:10.1201/b10200-8
29. H Yu, L Zhang, L Li, C Zheng, L Guo, W Li, P Sun, L Qin: Recent development and future prospects of antimicrobial metabolites produced by endophytes. Microbiol Res 165 (6), 437-449 (2010)
doi:10.1016/j.micres.2009.11.009
30. F R Murray, G C M Latch, D B Scott: Surrogate transformation of perennial rye grass, Lolium perenne, using genetically modified Acremonium endophyte. Mol Gen Genet 233, 1-9 (1992)
doi:10.1007/BF00587554
31. G Berg, A Krechel, F Faltin, A Ulrich, J Hallmann, R Grosch: Endophytes: a new source for environmental biotechnology .In: Abstracts of 10th international symposium on microbial ecology ISME-10, ''Microbial Planet: subsurfacetospace'', Cancun, Mexico, August 22-27, (2004)
32. S A Smith, D C Tank, L A Boulanger, C A Bascom-Slack, K Eisenman, B Babbs, K Fenn, J S Greene, B D Hann, J Keehner, E G Kelley-Swift, V Kembaiyan, S J Lee, P Li, D Y Light, E H Lin, C Ma, E Moore, M A Schorn, D Vekhter, P N Nunez, G Strobel, M J Donoghue, S A Strobel: Bioactive endophytes support intensified exploration and conservation. PLoS ONE 3, e3052 (2008)
doi:10.1371/journal.pone.0003052
33. R X Tan, W X Zau: Endophytes: A rich source of functional metabolites. Nat Prod Rep 18, 448-459 (2001)
doi:10.1039/b100918o
34. G A Strobel, B Daisy, U Castillo, J Harper: Natural products from endophytic fungi. J Nat Prod 67, 257- 268 (2004)
doi:10.1021/np030397v
35. H W Zhang, Y C Song, R X Tan: Biology and chemistry of endophytes. Nat Prod Rep 23, 753-771 (2006)
doi:10.1039/b609472b
36. A A L Gunatilaka: Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity and implications of their occurrence. J Nat Prod 69, 509-526 (2006)
doi:10.1021/np058128n
37. B Guo, Y Wang, X Sun, K Tang: Bioactive natural products from endophytes: A review. Appl Biochem Microbiol 44, 136-142 (2008)
doi:10.1134/S0003683808020026
38. J Y Li, J K Harper, D M Grant, B O Tombe, B Bashyal, W M Hess, G A Strobel: Ambuic acid, a highly functionalized cyclohexenone with antifungal activity from Pestalotiopsis sp. and Monochaetia sp. Phytochemistry 56 (5), 463-468 (2001)
doi:10.1016/S0031-9422(00)00408-8
39. G Ding, Y Li, S Fu, S Liu, J Wei, Y Che: Ambuic acid and torreyanic acid derivatives from the endolichenic fungus Pestalotiopsis sp. J Nat Prod 72, 182-186 (2009)
doi:10.1021/np800733y
40. J Nakayama, Y Uemura, K Nishiguchi, N Yoshimura: Ambuic Acid Inhibits the Biosynthesis of Cyclic Peptide Quormones in Gram-Positive Bacteria. Antimicrob Agents Chemother 53 (2), 580-586 (2009)
doi:10.1128/AAC.00995-08
41. G A Strobel, E Ford, J Worapong, J K Harper, A M Arif, D M Grant, P C Fung, R M W Chau: Isopestacin, an isobenzofuranone from Pestalotiopsis microspora, possessing antifungal and antioxidant activities. Phytochemistry 60, 179-183 (2002)
doi:10.1016/S0031-9422(02)00062-6
42. J K Harper, A M Arif, E J Ford, G A Strobel, J A Porco, D P Tomer, K L Oneill, E M Heider, D M Grant: Pestacin: a 1,3-dihydroisobenzofuran from Pestalotiopsis microspora possessing antioxidant and antimycotic activities. Tetrahedron 59, 2471- 2476 (2003)
doi:10.1016/S0040-4020(03)00255-2
43. J Y Li, G A Strobel: Jesterone and hydroxy-jesterone anti-oomycete cyclohexenenone epoxides from the endophytic fungus Pestalotiopsis jesteri. Phytochemistry 57, 261-265 (2001)
doi:10.1016/S0031-9422(01)00021-8
44. E Li, L Jiang, L Guo, H Zhang, Y Che: Pestalachlorides A-C, antifungal metabolites from the plant endophytic fungus Pestalotiopsis adusta. Bioorg Med Chem 16 (17), 7894-7899 (2008)
doi:10.1016/j.bmc.2008.07.075
45. G Ding, S Liu, L Guo, Y Zhou, Y Che: Antifungal metabolites from the plant endophytic fungus Pestalotiopsis foedan. J Nat Prod 71, 615-618 (2008)
doi:10.1021/np070590f
46. L Liu, S Liu, X Chen, L Guo, Y Che: Pestalofones A-E, bioactive cyclohexanone derivatives from the plant endophytic fungus Pestalotiopsis fici. Bioorg Med Chem 17 (2), 606-613 (2009)
doi:10.1016/j.bmc.2008.11.066
47. Z Huang, X Cai, C Shao, Z She, X Xia, Y Chen, J Yang, S Zhou, Y Lin: Chemistry and weak antimicrobial activities of phomopsins produced by mangrove endophytic fungus Phomopsis sp. ZSU-H76. Phytochemistry 69 (7), 1604 -1608 (2008)
doi:10.1016/j.phytochem.2008.02.002
48. Q Y Xu, Y J Huang, Z H Zheng, S Y Song, Y M Zhang, and W J Su: Purification, elucidation and activities study of cytosporone B. Xiamen Daxue Xuebao, Ziran Kexueban 44 (3), 425 - 428 (2005)
49. B Elsaesser, K Krohn, U Floerke, N Root, H J Aust, S Draeger, B Schulz, S Antus, T Kurtan: X-ray structure determination, absolute configuration and biological activity of phomoxanthone A. Eur J Org Chem 4563-4570 (2005)
doi:10.1002/ejoc.200500265
50. J Q Dai, K Krohn, U Florke, D Gehle, H J Aust, S Drarger, B Schulz, J Rheinheimer: Novel highly substituted biraryl ethers, phomosines D-G, isolated from the endophytic fungus Phomopsis sp. from Adenocarpus foliolosus. Eur J Org Chem 5100-5105 (2005)
doi:10.1002/ejoc.200500471
51. S H Wu, Y W Chen, H C Shao, L D Wang, Z Y Li, L Y Yang, S L Li, R Huang: Ten-membered lactones from Phomopsis sp., an endophytic fungus of Azadirachta indica. J Nat Prod 71, 731-734 (2008)
doi:10.1021/np070624j
52. D Weber, O Sterner, T Anke, S Gorzalczancy, V Martino, C Acevedo: Phomol, a new antiinflammatory metabolite from an endophyte of the medicinal plant Erythrina crista-galli. J Antibiot 57 (9), 559-563 (2004)
53. R W S Weber, R Kappe, T Paululat, E Mosker, H Anke: Anti-Candida metabolites from endophytic fungi. Phytochemistry 68, 886-892 (2007)
doi:10.1016/j.phytochem.2006.12.017
54. K A Hoberg, R L Cihlar, R A Calderone: Characterization of cerulenin-resistant mutants of Candida albicans. Infect Immun 51, 102-109 (1986)
55. G H Silva, H L Teles, H C Trevisan, Vanderlan da S Bolzani, M.C.M. Young, L. H. Pfenning, M. N. Eberlin, R. Haddad, C. M. Costa-Neto, A. R. Araujo: New bioactive metabolites produced by Phomopsis cassiae, an endophytic fungus in Cassia spectabilis. J Braz Chem Soc 16 (6B), 1463-1466 (2005)
doi:10.1590/S0103-50532005000800029
56. H Hussain, N Akhtar, S Draeger, B Schulz, G Pescitelli, P Salvadori, S Antus, T Kurtan, K Krohn: Biologically active secondary metabolites from fungi, 40. New bioactive 2,3-epoxycyclohexenes and isocoumarins from the endophytic fungus Phomopsis sp. from Laurus azorica. Eur J Org Chem 749-756 (2009)
doi:10.1002/ejoc.200801052
57. G H Silva, H L Teles, L MZanardi, M C M Young, M N Eberlin, R Hadad, L H Pfenning, C M Costa-Neto, I Castro-Gamboa, V S Bolzani, A R Araújo: Cadinane sesquiterpenoids of Phomopsis cassiae, an endophytic fungus associated with Cassia spectabilis (Leguminosae). Phytochemistry 67 (17), 1964-1969 (2006)
doi:10.1016/j.phytochem.2006.06.004
58. A M Hoffman, S G Mayer, G A Strobel, W M Hess, G W Sovocool, A H Grange, J K Harper, A M Arif , D M Grant, E G Kelley-Swift: Purification, identification and activity of phomodione, a furandione from an endophytic Phoma species. Phytochemistry 69 (4), 1049-1056 (2008)
doi:10.1016/j.phytochem.2007.10.031
59. W Zhang, K Krohn, H Egold, S Draeger, B Schulz: Diversity of antimicrobial pyrenophorol derivatives from an endophytic fungus, Phoma sp. Eur J Org Chem 4320-4328 (2008)
doi:10.1002/ejoc.200800404
60. A Basilio, M Justice, G Harris, G F Bills, J Collado, M de la Cruz, M T Dıez, P Hernandez, P Liberator, J Nielsen Kahn, F Pelaez, G Platas, D Schmatz, M Shastry, J R Tormo, G R Andersenand F Vicente: The discovery of moriniafungin, a novel sordarin derivative produced by Morinia pestalozzioides. Bioorg Med Chem 14, 560-566 (2005)
doi:10.1016/j.bmc.2005.08.046
61. J Collado, G Platas, G F Bills, A Basilio, F Vicente, J R Tormo, P Hernandez, M T Diez, F Pelaez : Studies on Morinia: recognition of Morinia longiappendiculata sp. nov. as a new endophytic fungus, and a new circumscription of Morinia pestalozzioides. Mycologia 98 (4), 616-627 (2006)
doi:10.3852/mycologia.98.4.616
62. W X Zou, J C Meng, H Lu, G X Chen, G X Shi, T Y Zhang, R X Tan: Metabolites of Colletotrichum gloeosporioides, an endophytic fungus in Artemisia mongolica. J Nat Prod 63 (11), 1529-1530 (2000)
doi:10.1021/np000204t
63. H Lu, W X Zou, J C Meng, J Hu, R X Tan : New bioactive metabolites produced by Colletotrichum sp., an endophytic fungus in Artemisia annua. Plant Science 51 (1), 67-73 (2000)
doi:10.1016/S0168-9452(99)00199-5
64. M L Inácio, G H Silva, H L Teles, H C Trevisan, A J Cavalheiro, V da S Bolzani, M C M Young, L H Pfenning, Á R Araújo : Antifungal metabolites from Colletotrichum gloeosporioides, an endophytic fungus in Cryptocarya mandioccana Nees (Lauraceae). Biochem Syst Ecol 34, 822-824 (2006)
doi:10.1016/j.bse.2006.06.007
65. H Hussain, K Krohn, S Draeger, B Schulz: Exochromone: structurally unique chromone dimer with antifungal and algicidal activity from Exophiala sp. Heterocycles 74, 331-337 (2007)
doi:10.3987/COM-07-S(W)10
66. G A Strobel, R V Miller, C M Miller, M M Condron, D B Teplow, W H Hess: Cryptocandin, a potent antimycotic from the endophytic fungus Cryptosporiopsis cf. quercina. Microbiology 145, 1919-1924 (1999)
doi:10.1099/13500872-145-8-1919
67. H M Noble, D Langley, P J Sidebottom, S J Lane, P J Fisher: An echinocandin from an endophytic Cryptosporiopsis sp. and Pezicula sp. in Pinus sylvestris and Fagus sylvatica. Mycol Res 95, 1439-1440 (1991)
doi:10.1016/S0953-7562(09)80401-2
68. J Y Li, G A Strobel, J Harper, E Lobkovsky, J Clardy: Cryptocin, a potent tetramic acid antimycotic from the endophytic fungus Cryptosporiopsis cf. quercina. Org Lett 2, 767-770 (2000)
doi:10.1021/ol000008d
69. F Pelaez, A Cabello, G Platas, M T Diez, A G del Val, A Basilio, I Martan, F Vicente, G F Bills, R A Giacobbe, R E Schwartz, J C Onishi, M S Meinz, G K Abruzzo, A M Flattery, L Kong, M B Kurtz: The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Syst Appl Microbiol 23, 333-343 (2000)
70. Y Seto, K Takahashi, H Matsuura, Y Kogami, H Yada, T Yoshihara, K Nabeta: Novel cyclic peptide, epichlicin, from the endophytic fungus, Epichloe typhina. Biosci Biotech Bioch 71 (6), 1470-1475 (2007)
doi:10.1271/bbb.60700
71. M L Macias-Rubalcava, B E Hernandez-Bautista, M Jimenez-Estrada, M C Gonzalez, A E Glenn, R T Hanlin, S Hernandez-Ortega, A Saucedo-Garcia, J M Muria-Gonzalez, A L Anaya : Naphthoquinone spiroketal with allelochemical activity from the newly discovered endophytic fungus Edenia gomezpompae. Phytochemistry 69 (5), 1185-1196 (2008)
doi:10.1016/j.phytochem.2007.12.006
72. B Kopcke, R W S Weber, H Anke: Galiellalactone and its biogenetic precursors as chemotaxonomic markers of the Sarcosomataceae (Ascomycota). Phytochemistry 60, 709-714 (2002)
doi:10.1016/S0031-9422(02)00193-0
73. R Abdou, K Scherlach, H M Dahse, I Sattler, C Hertweck: Botryorhodines A-D, antifungal and cytotoxic depsidones from Botryosphaeria rhodina, an endophyte of the medicinal plant Bidens pilosa. Phytochemistry 71,110-116 (2010)
doi:10.1016/j.phytochem.2009.09.024
74. K Krohn, M H Sohrab, T van Ree, S Draeger, B Schulz, S Antus, T Kurtin : Dinemasones A, B and C: New bioactive metabolites from the endophytic fungus Dinemasporium strigosum. Eur J Org Chem 5638-5646 (2008)
doi:10.1002/ejoc.200800688
75. J C Qin, Y M Zhang, J M Gao, M S Bai, S X Yang, H Laatschb: Bioactive metabolites produced by Chaetomium globosum, an endophytic fungus isolated from Ginkgo biloba. Bioorg Med Chem Lett 19 (6), 1572-1574 (2009)
doi:10.1016/j.bmcl.2009.02.025
76. W Pongcharoen, V Rukachaisirikul, S Phongpaichit, T Kühn, M Pelzing, J Sakayaroj and WC Taylor: Metabolites from the endophytic fungus Xylaria sp. PSU-D14. Phytochemistry 69, 1900-1902 (2008)
doi:10.1016/j.phytochem.2008.04.003
77. J H Park, G J Choi, H B Lee, K M Kim, H S Jung, S W Lee, K S Jang, K Y Cho, J C Kim: Griseofulvin from Xylaria sp. strain F0010, an endophytic fungus of Abies holophylla and its antifungal activity against plant pathogenic fungi. J Microbiol Biotechnol 15 (1), 112-117 (2005)
78. U Sommart, V Rukachaisirikul, Y Sukpondma, S Phongpaichit, J Sakayaroj, K Kirtikara: Hydronaphthalenones and a dihydroramulosin from the endophytic fungus PSU-N24. Chem Pharm Bull 56 (12), 1687-1690 (2008)
doi:10.1248/cpb.56.1687
79. M C Cafeu, G H Silva, H L Teles, V S Bolzani, A R Araujo, M C M Young, L H Pfenning: Antifungal compounds of Xylaria sp., an endophytic fungus isolated from Palicourea marcgravii (Rubiaceae). Quimica Nova 28 (6), 991-995 (2005)
80. X Liu, M Dong, X Chen, M Jiang, X Lv, J Zhou: Antimicrobial activity of an endophytic Xylaria sp.YX-28 and identification of its antimicrobial compound 7-amino-4-methylcoumarin. Appl Microbiol Biotechnol 78, 241-247 (2008)
doi:10.1007/s00253-007-1305-1
81.V Rukachaisirikul, J Kaeobamrung, W Panwiriyarat, Y Saitai, P Sukpondma, S Phongpaichit, J Sakayaroj: A new pyrone derivative from the endophytic fungus Penicillium paxilli PSU-A71. Chem Pharm Bull 55 (9), 1383-1384 (2007)
doi:10.1248/cpb.55.1383
82. F You, T Han, J Z Wu, B K Huang, L P Qin: Antifungal secondary metabolites from endophytic Verticillium sp. Biochem Syst Ecol 37, 162-165 (2009)
doi:10.1016/j.bse.2009.03.008
83. E K S Vijayakumar, K Roy, S Chatterjee, S K Deshmukh, B N Ganguli, H Kogler, H W Fehlhaber: Arthrichitin a new cell wall active metabolite from Arthrinium phaeospermum. J Org Chem 61, 6591-6593 (1996)
doi:10.1021/jo960769n
84. D Abbanat, M Leighton, W Maiese, E B Jones, C Pearce, M Greenstein: Cell wall active antifungal compounds produced by the marine fungus Hypoxylon oceanicum LL-15G256. I. Taxonomy and fermentation. J Antibiot 51, 296-302 (1998)
85. G Schlingmann, L Milne, D R Williams, G T Carter: Cell wall active antifungal compounds produced by the marine fungus Hypoxylon oceanium LL-15G256. II. Isolation and structure determination. J Antibiot 51, 303 -316 (1998)
86. D Albaugh, G Albert, P Bradford, V Cotter, J Froyd, J Gaughran, D R Kirsch, M Lai, A Rehnig, E Sieverding, S Silverman : Cell wall active antifungal compounds produced by the marine fungus Hypoxylon oceanicum LL-15G256. III. Biological properties of 15G256 gamma. J Antibiot 51, 317-322 (1998)
87. S H Wu, Y W Chen, S C Shao, L D Wang , Y Yu , Z Y Li , L Y Yang , S L Li, R Huang : Two new solanapyrone analogues from the endophytic fungus Nigrospora sp. YB-141 of Azadirachta indica. Chem and Biodivers 6, 79-85 (2008)
doi:10.1002/cbdv.200700421
88. L Chen, J Chen, X Zheng, J Zhang, X Yu: Identification and antifungal activity of metabolite of endophytic fungi isolated from Ilex cornuta. Nongyaoxue Xuebao 9 (2), 143-148 (2007)
89. J Dai, K Krohn, S Draeger, B Schulz: New naphthalene-chroman coupling products from the endophytic fungus, Nodulisporium sp. from Erica arborea. Eur J Org Chem 1564-1569 (2009)
doi:10.1002/ejoc.200801106
90. J Wang, Y Huang, M Fang, Y Zhang, Z Zheng, Y Zhao, W Su: Brefeldin A, a cytotoxin produced by Paecilomyces sp. and Aspergillus clavatus isolated from Torreya grandis. FEMS Immunol Med Microbiol 34, 51-57 (2002)
doi:10.1111/j.1574-695X.2002.tb00602.x
91. V Betina: Biological effects of the antibiotic Brefeldin A (Decumbin, cyanein, ascotoxin, synergisidin): A retrospective. Folia Microbiol 37, 3-11 (1992)
doi:10.1007/BF02814572
92. H Miyaoka, M Kajiwara: Enantioselective synthesis of the antifungal, antiviral and antimitotic compound, (+)-Brefeldin A. J Chem Soc Chem Comm 4, 483-484 (1994)
doi:10.1039/c39940000483
93. T Stenstad, G Husby: Brefeldin A inhibits experimentally induced AA amyloidosis. J Rheumatol 23 (1), 93-100 (1996)
94. S Ishii, M Nagasawa, Y Kariya, H J Yamamoto: Selective cytotoxic activity of brefeldin A against human tumor cell lines. J Antibiot 42, 1877-1878 (1989)
95. A Dasgupta, D W Wilson: Evaluation of the primary effect of brefeldin A treatment upon herpes simplex virus assembly. J Gen Virol 82, 1561-1567 (2001)
96. H Li, R Huang, Q Chen, T Sha, L Li, Z Zhao: Brefeldin A, a cytotoxin from an endophytic fungal strain of Eupenicillium brefeldianum isolated from Arisaema erubescens. Tianran Chanwu Yanjiu Yu Kaifa 20 (1), 24-27 (2008)
97. F W Wang, R H Jiao, A B Cheng, S H Tan, Y C Song: Antimicrobial potentials of endophytic fungi residing in Quercus variabilis and brefeldin A obtained from Cladosporium sp. World J Microb Biot 23 (1), 79-83 (2007)
doi:10.1007/s11274-006-9195-4
98. S F Brady, J Clardy: CR377, a new pentaketide antifungal agent isolated from an endophytic fungus. J Nat Prod 63 (10), 1447-1448 (2000)
doi:10.1021/np990568p
99. Y C Song, H Li, Y H Ye, C Y Shan, Y M Yang, R X Tan: Endophytic naphthopyrone metabolites are co-inhibitors of xanthine oxidase, SW1116 cell and some microbial growths. FEMS Microbiol Lett 241, 67-72 (2004)
doi:10.1016/j.femsle.2004.10.005
100. K Krohn, S F Kouam, S Cludius-Brandt, S Draeger, B Schulz: Bioactive nitronaphthalenes from an endophytic fungus, Coniothyrium sp., and their chemical synthesis. Eur J Org Chem 3615-3618 (2008)
doi:10.1002/ejoc.200800255
101. S Kim, D S Shin, T Lee, K B Oh: Periconicins, two new fusicoccane diterpenes produced by an endophytic fungus Periconia sp. with antibacterial activity. J Nat Prod 67, 448-450 (2004)
doi:10.1021/np030384h
102. D S Shin, M N Oh, H C Yang, K B Oh: Biological characterization of periconicins, bioactive secondary metabolites produced by Periconia sp. OBW-15. J Microbiol Biotechnol 15, 216-220 (2005)
103. J Dai, K Krohn, U Floerke, S Draeger, B Schulz, A Kiss-Szikszai, S Antus, T Kurtan, T van Ree: Metabolites from the endophytic fungus Nodulisporium sp. from Juniperus cedre. Eur J Org Chem 3498-3506 (2006)
doi:10.1002/ejoc.200600261
104. F W Wang, Z M Hou, C R Wang, P Li, D H Shi: Bioactive metabolites from Penicillium sp., an endophytic fungus residing in Hopea hainanensis. World J Microb Biot 24, 2143-2147 (2008)
doi:10.1007/s11274-008-9720-8
105. H L Teles, G H Silva, I Castro-Gamboa, V S Bolzani, J O Pereira, C M Costa-Neto, R Haddad, M N Eberlin, M C M Young, A R Araujo: Benzopyrans from Curvularia sp., an endophytic fungus associated with Ocotea corymbosa (Lauraceae). Phytochemistry 66 (19), 2363-2367 (2005)
doi:10.1016/j.phytochem.2005.04.043
106. J Y Liu, Y C Song, Z Zhang, L Wang, Z J Guo, W X Zou, R X Tan: Aspergillus fumigatus CY018, an endophytic fungus in Cynodon dactylon as a versatile producer of new and bioactive metabolites. J Biotechnol 114 (3), 279-287 (2004)
doi:10.1016/j.jbiotec.2004.07.008
107. C L Zhang, B Q Zheng, J P Lao, L J Mao, S Y Chen, C P Kubicek, F C Lin: Clavatol and patulin formation as the antagonistic principle of Aspergillus clavatonanicus, an endophytic fungus of Taxus mairei. Appl Microbiol Biotechnol 78, 833-840 (2008)
doi:10.1007/s00253-008-1371-z
108. Y Zhang, X M Li, C Y Wang, B G Wang: A new naphthoquinoneimine derivative from the marine algal-derived endophytic fungus Aspergillus niger EN-13. Chin Chem Lett 18 (8), 951-953 (2007)
doi:10.1016/j.cclet.2007.05.054
109. Y Zhang, S Wang, X M Li, C M Cui, C Feng, B G Wang : New sphingolipids with a previously unreported 9-methyl-C20-sphingosine moiety from a marine algous endophytic fungus Aspergillus niger EN-13. Lipids 42 (8), 759-764. (2007)
doi:10.1007/s11745-007-3079-8
110. W Zhang, K Krohn, S Draeger, B Schulz: Bioactive isocoumarins isolated from the endophytic fungus Microdochium bolleyi. J Nat Prod 71, 1078-1081 (2008)
doi:10.1021/np800095g
111. F W Wang, Y H Ye, J R Chen, X T Wang, H L Zhu, Y C Song, R X Tan: Neoplaether, a new cytotoxic and antifungal endophyte metabolite from Neoplaconema napellum IFB-E016. FEMS Microbiol Lett 261 (2), 218-223 (2006)
doi:10.1111/j.1574-6968.2006.00358.x
112. S Loesgen, J Magull, B Schulz, S Draeger, A Zeeck: Isofusidienols: Novel chromone-3-oxepines produced by the endophytic fungus Chalara sp. Eur J Org Chem 698-703 (2008)
doi:10.1002/ejoc.200700839
113. W Zhang, K Krohn, Z Ullah, U Flörke, G Pescitelli, L D Bari, S Antus, T Kurtán, J Rheinheimer, S Draeger, B Schulz: New mono- and dimeric members of the secalonic acid family: blennolides A-G isolated from the fungus Blennoria sp. Chem-Eur J 4913-4923 (2008)
doi:10.1002/chem.200800035
114. H L Teles, R Sordi, G H Silva, I Castro-Gamboa, V S Bolzani, L H Pfenning, L M de Abreu, C M Costa-Neto, C M M Young, A R Araujo: Aromatic compounds produced by Periconia atropurpurea, an endophytic fungus associated with Xylopia aromatica. Phytochemistry 67 (24), 2686-2690 (2006)
doi:10.1016/j.phytochem.2006.09.005
115. M A Cabello, G Platas, J Collado, M T Dıez, I Martin, F Vicente, M Meinz, J C Onishi, C Douglas, J Thompson, M B Kurtz, R E Schwartz, G F Bills, R A Giacobbe, G K Abruzzo, A M Flattery, L Kong, F Pelaez: Arundifungin, a novel antifungal compound produced by fungi: biological activity and taxonomy of the producing organisms. Int Microbiol 4, 93-102 (2001)
116. S M Mandala, R A Thornton, M, Rosenbach, J Milligan, M Garcia-Calvo, H G Bull, M B Kurtz: Khafrefungin, a novel inhibitor of sphingolipid synthesis. J Biol Chem 272 (51), 32709-32714 (1997)
doi:10.1074/jbc.272.51.32709
117. J AGorman, L P Chang, J Clark, D R Gustavson, K S Lam, S W Mamber, D Pirnik, C Ricca, P B Fernandes, J O'Sullivan: Ascosteroside, a new antifungal agent from Ascotricha amphitricha. I. Taxonomy, fermentation and biological activities. J Antibiot 40, 547-552 (1996)
118. J Onishi, M Meinz, J Thompson, J Curotto, S Dreikorn, M Rosenbach, C Douglas, G Abruzzo, A Flattery, L Kong, A Cabello, F Vicente, F Pelaez, M T Dıez, I Martin, G F Bills, R Giacobbe, A Dombrowski, R Schwartz, S Morris, G Harris, A Tsipouras, K Wilson, M B Kurtz: Discovery of novel antifungal (1,3)- beta-D-glucan synthase inhibitors. Antimicr Agents Chemother 44, 368- 377 (2000)
doi:10.1128/AAC.44.2.368-377.2000
119. L Sparapano, G Bruno, O Fierro, A Evidente: Studies on structure-activity relationship of sphaeropsidins A-F, phytotoxins produced by Sphaeropsis sapinea f. sp. cupressi. Phytochemistry 65, 189-198 (2004)
doi:10.1016/j.phytochem.2003.11.006
120. S Zhou, G R Stanosz: Relationships among Botryosphaeria species and associated anamorphic fungi inferred from the analyses of ITS and 5.8S rDNA sequences. Mycologia 93, 516 -527 (2001)
doi:10.2307/3761737
121. K Krohn, U Florke, M S Rao, K Steingrover, H J Aust, S Draeger, B Schulz: Metabolites from fungi 15. new isocoumarins from an endophytic fungus isolated from the Canadian thistle Cirsium arvense. Nat Prod Lett 15 (5), 353-361 (2001)
doi:10.1080/10575630108041303
122. K Krohn, M H Sohrab, S Draeger, B Schulz: New pyrenocines from an endophytic fungus. Nat Prod Commun 3(10), 1689-1692 (2008)
123. G A Strobel, E Dirksie, J Sears, C Markworth: Volatile antimicrobials from a novel endophytic fungus. Microbiol 147, 2943-2950 (2001)
124. J Worapong, G A Strobel, B H Daisy, U Castillo, G Baird, W M Hess: Muscodor roseus sp. nov. an endophyte from Grevillea pteridifolia. Mycotaxon 81, 463-475 (2002)
125. A M Mitchell, G A Strobel, E Moore, R Robison, J Sears: Volatile antimicrobials from Muscodor crispans, a novel endophytic fungus. Microbiology 156, 270-277 (2010)
doi:10.1099/mic.0.032540-0
126. I Atmosukarto, U Castillo, W M Hess, J Sears, G Strobel : Isolation and characterization of Muscodor albus I-41.3s, a volatile antibiotic producing fungus. Plant Sci 169, 854-861 (2005)
doi:10.1016/j.plantsci.2005.06.002
127. J Mercer, J I Jimenez: Control of fungal decay of apples and peaches by the biofumigant fungus Muscodor albus. Post Harvest Biol Tech 31, 1-8 (2004)
doi:10.1016/j.postharvbio.2003.08.004
128. J Mercier, D Manker: Biocontrol of soil-borne disease and plant growth enhancement in green house soilless mix by the volatile-producing fungus Muscodor albus. Crop Prot 24, 355-362 (2005)
doi:10.1016/j.cropro.2004.09.004
129. M Stinson, N K Zidack, G A Strobel, B Jacobsen: Mycofumigation with Muscodor albus and Muscodor roseus for control of seedling diseases of sugar beet and verticillum wilt of eggplant. Plant Dis 87, 1349-1354 (2003)
doi:10.1094/PDIS.2003.87.11.1349
130. B J Jacobsen, N K Zidack, G A Strobel, D Ezra, E Grimme, A M Stinson: Mycofumigation with Muscodor albus for control of soil borne microorganisms. In: Multitrophic interactions in soil. IOBC wprs Bulletin 27, 103-113 (2004)
131. N L Owen, N Hundley: Endophytes - the chemical synthesizers inside plants. Sci Prog 87 (2): 79-99 (2004)
doi:10.3184/003685004783238553
132. K L Higgins, A E Arnold, J Miadlikowska, S D Sarvate, F Lutzoni: Phylogenetic relationships, host affinity, and geographic structure of boreal and arctic endophytes from three major plant lineages. Mol Phylogenet Evol 42, 543-555 (2006)
doi:10.1016/j.ympev.2006.07.012
133. T S Suryanarayanana, N Thirunavukkarasu, M B Govindarajulub, F Sasse, R Jansen, T S Murali : Fungal endophytes and bioprospecting. Fungal Biol Rev 23, 9-19 (2009)
doi:10.1016/j.fbr.2009.07.001
134. H BBode, B Bethe, R Höfs, A Zeek: Big effects from small changes: possible ways to explore nature's chemical diversity. Chem Bio Chem 3, 619-627 (2002)
doi:10.1002/1439-7633(20020703)3:7<619::AID-CBIC619>3.0.CO;2-9
135. M S Turner, R H Drew, J R Perfect: Emerging echinocandins for treatment of invasive fungal infections. Expert Opin Emerg Drugs 11 (2), 231-250 (2006)
doi:10.1517/14728214.11.2.231
Abbreviations: mcg: microgram, ml: milliliter, AIDS: Acquired Immuno Deficiency Syndrome, MIC: Minimum Inhibitory Concentration, sp: species, IC50: half maximal inhibitory concentration, EC50: half maximal effective concentration, mg: milligram, mm: millimeter, ATCC: American Type Culture Collection, VOC: Volatile Organic Compound
Key Words: Antifungal compound, Endophytic fungi, Coelomycetes, Ascomycetes, Hyphomycetes, Unidentified Fungus, Volatile Organic Compounds, Review
Sent correspondence to: Sunil Kumar Deshmukh, Department of Natural Products, Piramal Life Sciences Limited, 1, Nirlon Complex, Off Western Express Highway, Near NSE Complex, Goregaon (East), Mumbai 400 063 India, Tel: 91-22-30818819, Fax: 91-22-3081-8703, E-mail:sunil.deshmukh@piramal.com