<em>Alternaria</em> species: endophytic fungi as alternative sources of bioactive compounds
10.6092/issn.2531-7342/8468
I funghi endofiti delle piante sono ricche fonti di metaboliti bioattivi. In particolare le specie appartenenti al gen. Alternaria producono una serie di molecole ad azione antimicrobica, antiossidante, anti HIV, antitumorale e antidiabetica. Nel presente lavoro vengono esaminate le piante associate alle specie di Alternaria e vengono riportati i composti bioattivi prodotti e la loro attività.
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2531-7342
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Gustavo Santoyo
Italian Journal of Mycology
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<em>Alternaria</em> species: endophytic fungi as alternative sources of bioactive compounds
Text.Serial.Journal
https://italianmycology.unibo.it/
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Articles
2018-07-24
2018-07-24
2018-01-29
2020-01-20
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Ital J Mycol
Gustavo Santoyo
2018/07/24
10.6092/issn.2531-7342/8468
40
Universidad Michoacana de San Nicolás de Hidalgo
2531-7342
HIV
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<em>Alternaria</em> species: endophytic fungi as alternative sources of bioactive compounds
https://italianmycology.unibo.it/article/download/8468/8238
47
D. Eram, M. Arthikala, G. Melappa, G. Santoyo                Italian Journal of Mycology vol. 47 (2018) ISSN 2531-7342
DOI: https://doi.org/10.6092/issn.2531-7342/8468




 Alternaria species: endophytic fungi as
 alternative sources of bioactive compounds
 ___________________________________________________________
  Daniya Eram1, Manojkumar Arthikala2, Govindappa Melappa1 and Gustavo
                                                     Santoyo3

 1Department    of Biotechnology, Dayananda Sagar College of Engineering, Shavige Malleshwara Hills,
 Kumaraswamy Layout, Bengaluru-560 078, Karnataka, India.
 2Ciencias Agrogenómicas, Escuela Nacional de Estudios Superiores, León, Universidad Nacional

 Autónoma de México (UNAM), C.P.-37684, Mexico.
 3Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo,

 Morelia, Michoacán, Mexico

 Correspondig Author e-mail: dravidateja07@gmail.com, drgovindappa-bt@dayanandasagar.edu

 Abstract

      Fungal endophytes are a rich source of functional metabolites. In particular, the different species of the
      genus Alternaria stand out for their arsenal of metabolites, which have roles as antimicrobial molecules,
      antioxidants; as well as activities against HIV or cancer or diabetes. This review will highlight on selected
      aspects of the fungal endophytes of Alternaria species: their widespread distribution, and the role of
      their metabolites with pharmaceutical or agronomical importance. The family plants associated with
      Alternaria species, their bioactive compounds and biological activity to date are examined.

      Keywords: Alternaria species; metabolites; antimicrobials; cancer; diabetes; HIV


 Riassunto

      I funghi endofiti delle piante sono ricche fonti di metaboliti bioattivi. In particolare le specie appartenenti
      al gen. Alternaria producono una serie di molecole ad azione antimicrobica, antiossidante, anti HIV,
      antitumorale e antidiabetica. Nel presente lavoro vengono esaminate le piante associate alle specie di
      Alternaria e vengono riportati i composti bioattivi prodotti e la loro attività.

      Parole chiave: Alternaria spp.; metaboliti; azione antimicrobica; cancro; diabete; HIV

 Introduction

 Endophytes are the micro-organisms that colonize the inside of the plant parts, without having any
 negative impact on the host (Arnold et al., 2003), and these contribute resistance against both biotic
 (Breen, 1994; Schulz et al., 1999; Dingle and McGee, 2003) and abiotic stresses (Siegel et al.,
 1990; West, 1994). The researchers found endophytic fungi in almost all studied plants and thus it
 implies an important component of plant micro-ecosystem (Strobel, 2006). In addition, the

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DOI: https://doi.org/10.6092/issn.2531-7342/8468



 endophytes impart resistance against plant pathogens and herbivores and they are also able to
 produce known or unknown pharmaceutical and agricultural important bioactive compounds. Most
 of endophytic organism bioactive compounds act as plant defence molecules and some of them are
 using to treat various human diseases (Owen and Hundley, 2004). Endophytic fungi from Muscador
 albus of rainforest plant are able to produce fumigant agent against stored grain pests (Strobel,
 2006; Strobel et al., 2001). The endophytic fungi are able to produce many antimicrobial
 metabolites, such as colletotric acid (Zou et al., 2000) and griseofulvin (Park et al., 2005) reported
 from Alternaria species ubiquitous fungal genus including saprobic, endophytic and pathogenic
 species. Alternaria species are associated with a wide variety of substrates including seeds, plants,
 agricultural products, animals, soil and the atmosphere. Pathogenic species of Alternaria pose
 variety of phytopathological problems which results in yield losses in a wide range of crop plants.
 Several taxa are also important postharvest pathogens, causative agents of phaeohyphomycosis in
 immuno-compromised patients or airborne allergens. von Esenbeck (1816) originally described
 Alternaria, based on A. tenuis as the only species. Characteristics of the genus included the
 production of dark-coloured phaeodictyospores in chains, and a beak of tapering apical cells. von
 Keissler (1912) synonymised both A. tenuis and Torula alternata (Fries, 1832) with Alternaria
 alternata, due to ambiguities in Nees’s description of A. tenuis. Two additional genera,
 Stemphylium (Wallroth, 1833) and Ulocladium (Preuss, 1851) were subsequently described for
 phaeodictyosporichyphomycetes, further complicating the taxonomic resolution in this group of
 fungi. Several re-descriptions and revised criteria of these genera (Saccardo, 1886; Elliot 1917;
 Wiltshire, 1933, 1938; Joly, 1964) resulted in a growing number of new species. Results of a
 lifetime study on Alternaria taxonomy based on morphological characteristics were summarised by
 Simmons (2007), in which 275 Alternaria species were recognised. One species was transferred to
 the genus Prathoda and three new genera, Alternariaster, Chalastospora and Teretispora were
 segregated from genus Alternaria. Molecular studies revealed multiple non-monophyletic genera
 within the Alternaria complex and Alternaria species clades, however based on morpholigical
 characteristics it do not correlate to species-groups (de Hoog and Horré, 2002; Pryor and Bigelow,
 2003; Hong et al., 2005; Inderbitzin et al., 2006; Pryor et al. 2009; Runa et al., 2009; Lawrence et
 al., 2012). The A. alternata, A. brassicicola, A. infectoria, A. porri and A. radicina species groups
 were strongly supported by these studies and two new species-groups, A. sonchi (Hong et al., 2005)
 and A. alternantherae (Lawrence et al., 2012) and two new genera, Crivellia (Inderbitzin et al.,
 2006), Undifilum (Pryor et al., 2009) were described. The latest molecular revision of Alternaria
 (Lawrence et al., 2012) introduced two new species groups, A. panax and A. gypsophilae, and
 elevated eight species-groups to sections within Alternaria. The sexual phylogenetic Alternaria
 lineage, the A. infectoria species-group, did not get the status of section, in contrast to the eight
 asexual phylogenetic lineages in Alternaria. The Alternaria complex currently comprises the genera
 Alternaria, Chalastospora (Simmons, 2007), Crivellia, Embellisia, Nimbya, Stemphylium,
 Ulocladium, Undifilum and the recently described Sinomyces together with eight sections of
 Alternaria and the A. infectoria species-group. The present review focused on endophytic fungi,
 Alternaria species, their phytochemicals, biological activity and their plant hosts in detail.
 Spreading family
 Details of endophytic Alternaria species, hosts, natural compounds are represented in table 1. Their
 biological activities are briefly explained in figure 1. Endophytic fungi, Alternaria species been found in
 various plant species belonging to different families. Alternaria species in Taxus cuspidata, T.
 yunnanensis and T. chinensis var. mairei belonging to the Taxaceae family produce taxol, cladosporol
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DOI: https://doi.org/10.6092/issn.2531-7342/8468



 and paclitaxel which mainly exhibit anti-cancer/ anti-tumour properties (Vasundhara et al., 2016;
 Chen et al., 2009; Strobel et al., 1996; Kim and Ford, 1999; Tian et al., 2006; Zhou et al., 2007; Guo et
 al., 2009; Wu et al., 2011). Li and co-workers (2016a) obtained 940 isolates from different tissues of
 Zanthoxylum bungeanum and were grouped into 93 morphotypes, 43 species, and 23 genera. Potent
 antioxidant and antimicrobial activity was observed with extract of A. alternata, isolated from bark of
 Aegle marmelos (Mani et al., 2015; Selvi and Balagengatharathilagam, 2014) and Phellodendron
 amurense (Duan, 2009) belonging to Rutaceae family.
 Alternaria alternata (isolated from Eugenia jambolana) extract exhibited strong antibacterial property
 against MDR (Multi-Drug Resistance) (Yadav et al., 2016). Salvia miltiorrhiza (Tian et al., 2017; Lou et
 al., 2016), Salvia przewalskii (Wang et al., 2014) and Ocimum sanctum (Chowdhary and Kaushik, 2015)
 of Lamiaceae family have exhibited Alternaria species and it showed anti-bacterial and anti-
 phytopathogenic property.
 Alternaria tenuissima was reported from bark of Erythrophleum fordii (Fang et al., 2012) able to
 produce cyclopeptides, and also from leaves of Acacia magnum produce alternariol monomethyl ether
 and α, β- dehydrocurvularin. These biomolecules has been reported to have inhibitory effect on
 Magnaporthe grisea appressorium development (Jeon et al., 2010).
 Alternaria brassicola isolated from Malus halliana (Rosaceae) producing alternariol, alternariol 9-
 methyl ether, altechromone A, herbarin A, cerevisterol, 3β, 5α- 22E, 24R)-3,5-dihydroxyergosta-7,22-
 dien-6-one and 3β, 5α-dihydroxy- (22E,24R)-ergosta-5,8,22-trien-7-one are antimicrobial agents (Guo
 et al., 2009). A phenylpropene known as eugenol was identified in Alternaria species isolated from
 Rosa damacaena (Rosaceae) (Kaul et al., 2008). Anti-insecticidal podophyllotoxin was noticed in
 extract of Alternaria species isolated from Sabina vulgaris (Cupressaceae) (Lu et al., 2006).
 The Alternaria species was isolated from root of marine semi-mangrove plant, Myoporum bontioides
 (Scrophulariaceae) able to produce cyclohexenone, cyclopentenone and xanthone and were reported
 to be a strong antioxidant and antimicrobial agents (Wang et al., 2014). Antibacterial agent altenusin
 was noticed in the extract of Alternaria species, endophytic fungi of Sonneratia alba (Lythraceae) (Kjer
 et al., 2009).
 Endophyte, Alternaria species was also isolated from Ginkgo biloba of Ginkoaceae (Qin et al., 2009) and
 extracts showed strong antifungal activity (Xiao et al., 2013). Alternaria species isolated from phloem
 of Catharanthus roseus (Apocynaceae) had the ability to produce vinblastine (Zhang et al., 1998).
 Podophyllotoxin was identified from Alternaria neesex of Sinopodophyllum hexandrum (Berberidaceae)
 (Li, 2007; Cao et al., 2007; Yang et al., 2003) and also from Alternaria species obtained from Sabina
 vulgaris (Lu et al., 2006). Paclitaxel was isolated from Alternaria species (Taxus cuspidata), Alternaria
 species (Ginkgo biloba), Alternaria alternata (Taxus chinensis var mairei) (Strobel et al., 1996; Kim et
 al., 1999; Tian et al., 2006).
 The endophytic Alternaria species were also reported from Quercus emoryi of Fagaceae (Bashyal et al.,
 2014), Tabebuia argentea of Bignoniaceae (Channabasava and Govindappa, 2014), Viscum album of
 Santalaceae (Govindappa et al., 2015), Trixis vauthieri of Asteraceae (Cota et al., 2008), Ficus carica of
 Moraceae (Feng and Ma, 2010), Denderonephthya hemprichi of Nephtheidaceae (Shaaban et al.,
 2012), Polygonum senegalense of Polygonaceae (Aly et al., 2008), Azadirachta indica of Meliaceae
 (Taware and Rajurkar, 2015), Aegiceras corniculatum of Primulaceae (Huang et al., 2011), Laurencia
 species of Rhodomelaceae (Gao et al., 2009), Paeonia delavayi of Paeoniaceae (Wu et al., 2011),
 Maytenus hookeri of Celastraceae (Yuan et al., 2008), Tylophora indica of Apocynaceae (Kumar et al.,
 2011) and Vitis vinifera of Vitaceae family (Shi et al., 2012).



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DOI: https://doi.org/10.6092/issn.2531-7342/8468




 Fig. 1. Important phytochemicals from endophytic fungi, Alternaria species and their biological activity
 Fig. 1. Importanti prodotti fitochimici da specie di Alternaria e loro attività biologica.



 Antimicrobial molecules
 Alternaria species or A. alternata from Camptotheca acuminata (Ding et al., 2006), Achyranthus aspera,
 Adhatoda zeylanica, Aegle marmelos, Leucas aspera, Azadirachta indica (Selvi and
 Balagengatharathilagam, 2014), A. raphami from Vitax negundo (Monali et al., 2013), A.tenussima from
 Ricinus communis (Sandhu et al., 2014a) were the promising antibacterial compounds against different
 pathogenic bacterial species.
 Extracts of Alternaria species isolates of Tephrosia purpurea (Luo et al., 2015) and Opuntia humifusa
 (Silva-Hughes, 2015), A. alternata from Suaeda martiana, Sueada monoica (Kalyanasundaram et al.,
 2015), A. solani from Heptacdium miconioides (Wang et al., 2016), Altrnaria species had shown strong
 antifungal activity against plant pathogens. The Alternaria species of Garcinia plant exhibited antiviral
 activity (Wiyakrutta et al., 2004; Phongpaichit et al., 2007). Alternaria species from Mllotus
 philippinensis (Gangwar et al., 2015), Loranthus (Govindappa et al., 2011), Artemissia species
 (Cosoveanu et al., 2016) extract showed strong antimicrobial activity.
 Antioxidant molecules
 Oxidative stress has been identified as the root cause of the development and progression of several
 diseases. Supplementation of exogenous antioxidants or boosting endogenous antioxidant defences of
 the body is a promising way of combating the undesirable effects of reactive oxygen species (ROS)
 induced oxidative damage. Many medicinal plants contain large amounts of antioxidants other than
 vitamin C, E and carotenoids (Javanmardi et al., 2003). Antioxidants are molecules that can delay or
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DOI: https://doi.org/10.6092/issn.2531-7342/8468



 prevent an oxidative reaction (Velioglu et al., 1998) catalysed by free radicals. This antioxidant effect is
 mainly due to the presence of phenolic components such as flavonoids (Pietta et al., 1998), phenolic
 acids and phenolic diterpenes (Shahidi et al., 1992). Antioxidants such as Butylated Hydroxy-Anisol
 (BHA), Butylated Hydroxy-Toluene (BHT) protect plants against oxidative assault (Dziezak, 1986)
 either by binding to metallic ions, eliminating free radicals or by decomposing peroxides (Matook,
 2005). Despite the availability of synthetic antioxidants, present research seeks at discovering new
 natural antioxidant compounds that may play a role in oxidative stress related disorders (Agbor et al.,
 2005). Epidemiological studies (Urquiaga and Leighton, 2000; Halliwell, 1994) have showed that
 decreases in the incidence of chronic diseases in some populations were related to the consumption of
 fruits and vegetables. Antioxidants such as saponins, phenolic compounds, anthraquinones, steroids,
 cardiac glycosides and tannins are produced by endophytic Alternaria species found in Aegle marmelos
 (Selvi and Balagengatharathilagam, 2014) and Dibenzo-α-pyrones (1–7) in Salvia miltiorrhiza Bunge
 (Tian et al., 2017). The crude extracts of A. alternata from Coffea arabica (Fernandes et al., 2009),
 Alternaria species from Mussaenda luteola (Gunasekharan et al., 2017) showed strong antioxidant
 activity.
 Anti-diabetic molecules
 In humans, diabetes mellitus is considered as one of the five leading causes of death in the world
 (Joseph and Jini, 2011). Diabetes mellitus is a major global health concerning with a projected rise in
 prevalence from 171 million in 2000 to 366 million in 2030 (Shaw et al., 2010). It is a syndrome of
 disordered metabolism, usually due to a combination of hereditary and environmental causes,
 resulting in abnormally high blood sugar levels (hyperglycemia) (Patel et al., 2012). Being a major
 degenerative disease, diabetes is found in all parts of the world and increasing rapidly and thus it is
 the third most lethal disease of mankind (Ogbonnia et al., 2008). It is the most common endocrine
 disorder, affecting 16 million individuals in the United States alone and as many as 200 million
 individuals worldwide. Diabetes has been a clinical model for general medicine (Sharma et al., 2012).
 Complementary and alternative medicine involves the use of herbs and other dietary supplements as
 alternatives to mainstream western medical treatment. A recent study has estimated that up to 30% of
 patients with diabetes mellitus use complementary and alternative medicine (Raman et al., 2012).
 Alternaria species can be an excellent source for production of anti-diabetic molecules. Lectin (N-
 acetyl-Galactosamine) produced by endophytic Alternaria species of Viscum album been characterized
 to process has anti-diabetic properties (Govindappa et al., 2015). In another study, Alternaria species
 from Phyllanthus emblica fruits (Singh et al., 2017) and Morus alba (Zheng et al., 2014) exhibited
 strong inhibitory effect on diabetic enzymes.
 Anti-HIV molecules
 Since the first cases of AIDS were identified in 1981 in the United States. AIDS has become the largest
 and most devastating public health pandemic of our time, and has infected nearly 70 million people
 and left 25 million dead, and around the world, the number of people living with HIV is about 36.7
 million. Combination therapy of anti-HIV drugs now available has improved the quality of life and life-
 span of HIV/AIDS patients. Emergence of HIV drug resistance, side effects and the need for long-term
 antiretro-viral treatment are the main causes for the failure of anti-retroviral therapy (ART).
 Continuous development of new anti-HIV agents, targets and therapy appear to be inevitable. In some
 countries, traditional medicine is used to meet primary health care needs and to treat AIDS patients
 (Harnett et al., 2005). Natural products are the most consistently successful source in drug discovery,
 and may offer more opportunities to find anti-HIV drugs or lead compounds. Many compounds with an
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 anti-HIV-1 effect have been screened out from natural products and discovered to inhibit HIV at nearly
 all stages of the viral life cycle (Wang et al., 2004). They include alkaloids, sulphated polysaccharides,
 polyphenolics, flavonoids, coumarins, phenolic, tannins, triterpenes, lectins, phloroglucinols, lactones,
 iridoids, depsidones, O-caffeoyl derivatives, lignans, ribosome-inactivating proteins, saponins,
 xanthones, naph-thadianthrones, photosensitisers, phosholipids, quinines and peptides (Ng et al.,
 1997; Vlietinck et al., 1998; Yang et al., 2001). Natural products provide a large reservoir for screening
 anti-HIV agents with novel structure and anti-viral mechanisms because of their structural diversity. A
 variety of natural products have been found to inhibit unique enzymes and proteins crucial to the life
 cycle of HIV, including efficient intervention with the reverse transcription process, virus entry,
 integrase and protease (De Clercq, 2000; Cos et al., 2004). But the mechanism of anti-HIV activity of
 many more natural products is still unknown.
 People living with HIV/AIDS often choose traditional or complementary and alternative medicine to
 complement or replace conventional treatment. The presence of multi-drug or even multiclass
 resistance in HIV also warrants the need to explore additional means to combat HIV and provide
 further justifications for the need of alternative and complementary medicines in the treatment of
 HIV/ AIDS. Most of the traditional systems of medicine in India include some form of ‘medicinal plant’,
 herbs or natural plant products. It is therefore not surprising that the activity of these traditional
 medicines against HIV can be scientifically analysed to deduce the role of natural plant products in
 their anti-HIV activities. A number of medicinal plants have been reported to have anti-HIV properties
 (Fritts et al., 2008). Over the past two decades, substantial progress has been made in research on the
 natural products possessing anti-HIV activity. A variety of secondary metabolites obtained from
 natural origin showed moderate to good anti-HIV activity.
 Endophytes present in various plants can also be a potential source for production of anti-HIV
 molecules (Singh et al., 2005). Altertoxins produced by A. tenussima shows a significant anti-HIV
 activity (Bashyal et al., 2014; Wellensiek et al., 2013). Partially purified coumarin extracts of Alternaria
 species from Calophyllum inophyllum) have inhibited the HIV-1 replicating proteins significantly
 (Govindappa et al., 2015). Perylnequinones isolated from A. tenussima of Quercus emoryi have shown
 potent HIV-1 inhibitors (Hudson et al., 1997).
 Anti-microbial molecules
 Endophytes, microorganism that reside in the tissue of living plants, are relatively understudied and
 potential source of novel natural products for exploitation in medicine, agriculture and industries
 (Sandhu et al., 2014b). The resistance of pathogenic microorganisms to drugs and antibiotics has
 become a major challenge in the health sector leading to reduction in drug effectiveness and economic
 wastage. This challenge has once again stirred up a need in scientific research and the discovery of
 new more effective antimicrobial metabolites becoming a major research interest. In recent years, the
 isolation of endophytic fungi and screening of antimicrobial activity has gained more attention
 (Strobel, 2003).
 The increase in the resistance of drugs by infectious pathogens as well as undesirable effects of certain
 antimicrobial agents indicates that there is an urgent need for novel and effective bioactive
 compounds with fresh modes of action which is what this study is aimed at achieving stated that
 during the last 20 years (Strobel, 2006; Porras-Alfaro and Bayman, 2011). It has been observed that
 much of the wealth of microbial biodiversity with novel biochemistry and secondary metabolite
 production resides in plant tissues. The endophytes of these plants, especially the Alternaria species
 produce a wide range of anti-microbial compounds.


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 Fischexanthone, an anti-fungal compound, is produced by endophytic Alternaria from root tissues of
 Myoporum bontioides (Li et al., 2016b). Strong anti-fungal activity was observed in Ficus carica due to
 the production of helvolic acid by the endophytic Alternaria (Feng and Ma, 2010). Cyclo-[L-Leu-trans-
 4-hydroxy-L-Pro-], Cyclo-(L- Phe-trans-4-hydroxy-L-Pro-), and Musetti et al. (2007) have produced
 Cyclo-(L-Ala-trans-4-hydroxy-L-Pro) in broth culture of the grapevine also exhibits anti-fungal activity.
 Xanalteric acids I and II produced in Somneratia alba exhibits weak anti-bacterial activity against
 multidrug-resistant Staphylococcus aureus (Kjer et al., 2009). Solanapyrones P–R (1–3), solanapyrones
 (4–6) and benzopyrones (7–9) produced in the root tissues of a Chinese herbal medicinal plant Salvia
 przewalskii also exhibits anti-bacterial activity (Xiao et al., 2014). Apart from these dibenzo-α-pyrones
 produced in Salvia miltiorrhiza (Danshan) due to endophytic Alternaria also shows anti-bacterial
 activity (Tian et al., 2017).
 Altersin produced by Alternaria shows broad anti-microbial activity (Hellwig et al., 2002; Fernandes et
 al., 2009). Alternusin produced by endophytic Alternaria species of Sonneratia alba exhibits anti-
 microbial activity against several additional multidrug-resistant bacterial and fungal strains (Kjer et
 al., 2009). Alternariol 9-methyl ether (AME) in Salvia miltiorrhiza (Lou et al., 2016); berberine in
 Phellodendron amurense (Duan, 2009); saponins, phenolic compounds, anthraquinones, steroids,
 cardiac glycosides and tannins in Aegle marmelos (Selvi and Balagengatharathilagam, 2014);
 pyrophen, rubrofusarin B, fonsecin, fonsecin B aurasperone A, aurasperone B, aurasperone C , and
 aurasperone F in Denderonephthya hemprichi (Shaaban et al., 2012); 7-epi-8-hydroxyaltertoxin I and
 6-epi-stemphytriol, stemphyperylenol and altertoxin I in Laurencia sp. (Gao et al., 2009); alternariol,
 alternariol 9-methyl ether, altechromone A, herbarin A, cerevisterol, 3β,5α-dihydroxy-(22E,24R)-
 ergosta-7,22-dien-6-one and 3β-hydroxy-(22E,24R)-ergosta-5,8,22-trien-7-one in Mallus haliana (Guo
 et al., 2009); alternariol, djalonensone, cerebroside B, cerebroside C, (2S, 3S, 4R, 2' R) -(2'-
 hydroxytetracosanoylamino) octadecane-1,3,4-triol, and mannitol in Paeonia delavayi (Wu et al.,
 2011) were reported to process anti-microbial activity. Gunasekharan et al. (2017), Srinivasan et al.
 (2015) have reported that Alternaria species extracts have inhibited the activity of pathogenic
 bacteria. Two new antimicrobial compounds, 10-oxo-10H-phenaleno[1,2,3-de] chromene-2-carboxylic
 acids, xanalteric acids I and II and 11 known secondary metabolites were obtained from Alternaria
 species extract (Sonneratia alba) and they are strong antibacterial compounds (Kjer et al., 2009). The
 potent antifungal activity was observed from Alternaria species extract isolated from Clerodendrum
 inerme (Gong et al., 2015).
 Anti-cancer molecules
 Cancer is considered one of the most common causes of human mortality worldwide. Progress made in
 cancer therapy has not been sufficient to a significantly lower annual death rate from most tumor
 types, and there is an urgent need for new strategies in cancer control (Mesnah et al., 1987). For
 centuries, people have been using plants for their therapeutic values. Today 85000 plants have been
 documented for therapeutic use globally (Liu and Wang, 2008). The World Health Organization (WHO)
 estimates that almost 75% of World’s population has therapeutic experience with herbal drugs. Cancer
 is one of the most widespread diseases in humans and presently there is a considerable scientific
 discovery of new anticancer agents from natural products (Kasabana and Hemini, 1998). The potential
 of using the natural products as anticancer drugs was recognized in 1950’s by U.S. Natural Cancer
 Institute (NCI) since 1950 major contributions have taken for the discovery of naturally occurring
 anticancer drugs (Cragg and Newman, 2005).
 In this sense, altertoxin IV showed significant anticancer activity was isolated from endophytic fungi
 Alternaria species of Broussonetia papyrifera (Zhang et al., 2016). Taxol is producing by Alternaria
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DOI: https://doi.org/10.6092/issn.2531-7342/8468



 species of Salacia oblonga (Roopa et al., 2015), Taxus cuspidata (Strobel et al., 1996), Ginkgo biloba
 (Kim et al., 1999), Corylus avellena (Michalczyk et al., 2014; Soliman and Raizada, 2013) and
 paclitataxel from Alternaria tenuissima (Ismaiel et al., 2017). Taxanes was isolated from Alternaria
 species of Taxus baccata (Staniek et al., 2010). Alternaria species have ability to produce paclitaxel or
 its analogues (Zhao et al., 2012; Chandra, 2012). Camptothecine (CPT) and its analogues 9-
 methoxycmptothecine (MCPT) and 10-hydroxycamptothecine (HCPT) produced by Alternaria
 alternata from Miquelia dentata (Shweta et al., 2013). Anticancer agent, coumarins were reported
 from Alternaria species which colinize Crotalaria pallida (Umashankar et al., 2015), lapachol from
 Alternaria species and A. alternata (Sadananda et al., 2011; Channabasava and Govindappa, 2014),
 podophyllotoxin from Alternaria species (S. hexandrum). Vinblastine and vincristine were produced
 from Alternaria species isolated from Catharanthus roseus (Guo and Kunming, 1998). Kaul et al. (2008)
 have reported the eugenol produced by Alternaria species of rose. Reveratrol isolated from Alternaria
 species of Vitis vinifera, Vitis quinquangularis, Polygonum cuspidatum (Shi et al., 2012) and cytotoxic
 compounds were isolated from Alternaria species of Polygonum senegalense (Aly et al., 2008).
 Alternariol metabolite from Alternaria species of Polygonum senegalense (Aly et al., 2008), Salvia
 miltiorrhiza (Lou et al., 2016) exhibit anti-cancer activity. Alternaria alternata (Cissus quadrangularis,
 Asclepias curassavica) extract had shown strong cytotoxicity activity (Tenguria and Firodiya, 2016).

 Discussion and future research

 Alternaria species are an abundant source of bioactive molecules, with promising roles to fight against
 pathogenic microbes or human diseases, such as diabetes, HIV and cancer. However, it is suggested
 that the work done in the future include a step to take a step forward to apply all these promising
 metabolites. It is known that the regulations in each country of the world are different for the clinical
 application of new compounds, but undoubtedly, researchers from each region should make an effort
 to achieve this goal for the benefit of humanity.
 Likewise, attention is needed within the basic research on different compounds that produce the
 endophytic fungi, Alternaria species and to identify environmental aspects that regulate their
 production, as well as their effectiveness when applied. The aspects of resistance in antimicrobial
 compounds are also an area, requires a continuous research, because new resistance mechanisms
 arise with new drugs. Large scale commercial productions of such biomolecules using biotechnological
 tools are also in urgent used. Therefore, it is a potential area for investigation and pharmaceutical
 applications.

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  Table 1. in supplementary file.




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