Critical Reviews in Microbiology, 2009; 35(3): 182–196 REVIEW ARTICLE Phoma Saccardo: Distribution, secondary metabolite production and biotechnological applications Mahendra Rai1, Prajakta Deshmukh1, Aniket Gade1, Avinash Ingle1, György J. Kövics2, and László Irinyi2 1 Department of Biotechnology, SGB Amravati University, Amravati, Maharashtra, India, and 2Debrecen University, Faculty of Agriculture, Department of Plant Protection, Debrecen, Hungary Abstract Phoma Sacc. is an ubiquitous fungus, which has been reported from plants, soil, human beings, animals, and air. Some species of Phoma like P. sorghina, P. herbarum, P. exigua var. exigua, P. macrostoma, P. glomerata, Phoma macdonaldii, Phoma tracheiphila, Phoma proboscis, P. multirostrata, and Phoma foveata secrete phytotoxin and anthraquinone pigments as secondary metabolites, which have great potential for the biological control of weeds, and can be exploited for the production of mycopesticides, agrophytochemicals, and dyes. Some other species produce pharmaceutically active metabolites, viz., Sirodesmins, Phomenoic acid, Phomenolactone, Phomadecalins, Phomactin A, Phomasetin, Squalestatin-1 (S1), and Squalestatin-2 (S2). The secondary metabolites secreted by some species of Phoma are antitumor, antimicrobial, and antiHIV. Equisetin and Phomasetin obtained from species of Phoma are useful against AIDS. The main goal of the present review is to discuss secondary metabolite production by species of Phoma and their utilization as antibiotics and as biocontrol agents. Keywords: Phoma; secondary metabolites; antibiotics; anthraquinones; pigments Introduction Fungi produce a chemically diverse array of metabolites, many of which are important indirectly for its growth and survival. Secondary metabolites are compounds produced by higher plants and fungi that are not essential to basic metabolism. hese compounds are generally produced following active growth, and often have unusual chemical structures. While some metabolites are found in many related fungi, others are only found in one or a few species. his restricted distribution implies a lack of general function of secondary metabolites in fungi (Vining 1990). Interestingly, six of the twenty most commonly prescribed medications are secondary metabolites of fungal origin. hese metabolites have been subjected to combinatorial chemistry following growth in selective media. Some metabolites are toxic to humans and animals. Yet others can modify the growth and metabolism of plants. he genus Phoma was introduced more than 170 years ago. More than 2000 species have been studied (Montel et al. 1991). It is ubiquitous genus and have been reported from wide variety of the hosts/substrates. Fungi of the genus Phoma are reported from diferent plants as phytopathogens (Jamaluddin et al. 1975; Bhowmik and Singh 1976; Raut 1977; Kamal and Singh 1979; Rai and Misra 1981; Rao and hirumalachar 1981; Boerema and Gruyter 1998, 1999; Kövics et al. 1999), as saprophytes from soils (Mathur and hirumalachar 1959; Dorenbosch 1970; Singh and Agarwal, 1973, 1974; Morgan-Jones and Burch 1988), aquatic and aerial environment (Rai and Rajak 1983a), marine environment (Sugano et al. 1991), entomopathogenic (Narendra and Rao 1974) and as opportunistic human pathogens (Rai 1989; Zaitz et al. 1997). Boerema and his colleagues have contributed signiicantly to the reclassiication and numerous other aspects of Phoma and Phoma-like fungi (Boerema 1964, 1976, 1984, 1985, 1986, 1993, 1997; Brewer and Boerema Address for Correspondence: M.K. Rai, Department of Biotechnology, S.G.B. Amravati University, Amravati, Maharashtra 444602, India. E-mail: mkrai123@redifmail.com; pmkrai@hotmail.com (Received 26 July 2008; revised 16 March 2009; accepted 17 April 2009) ISSN 1040-841X print/ISSN 1549-7828 online © 2009 Informa UK Ltd DOI: 10.1080/10408410902975992 http://www.informapharmascience.com/mcb Phoma Saccardo: Distribution, secondary metabolite production and biotechnological applications 1965; Boerema et al. 1965, 1968, 1971, 1973, 1977, 1981, 1994, 1996, 1997, 1999; 2004, Boerema and Höweler 1967; Boerema and Dorenbosch 1970, 1973; Boerema and Bollen 1975; Boerema and van Kesteren 1964, 1981; Boerema and Loerakker 1981, 1985; Gruyter and Noordeloos 1992; Gruyter et al. 1993, 1998; Noordeloos et al. 1993; Boerema and Gruyter 1998, 1999; Kövics and Gruyter 1995; Kövics et al. 1999). Cultural and morphological studies of Indian species of Phoma deined 20 broad morphological groups (Rai 1985, 1986a, 1986b, 1987, 1989, 2003; Rai and Rajak 1982a, 1982b, 1983a, 1983b, 1986a, 1986b, 1993; Rajak and Rai 1982, 1983a, 1983b, 1984, 1985). hese groups include P. pinodella (L.K. Jones) Morgan-Jones & K.B. Burch, P. medicaginis Malbr. & Roum. var. medicaginis, P. pomorum hüm. var. pomorum, P. herbarum Westend., P. exigua Desm. var. exigua, P. tropica R. Schneider & Boerema, P. glomerata (Corda) Wollenw. & Hochapfel, P. sorghina (Sacc.) Boerema et al. P. multirostrata (P.N. Mathur et al.) Dorenb. & Boerema var. multirostrata, P. capitulum V.H. Pawar et al., P. betae A.B. Frank, P. jolyana Piroz. & Morgan-Jones var. jolyana, P. imeti Brunaud, P. chrysanthemicola Hollós, P. complanata (Tode: Fr.) Desm., P. destructiva Plowr. var. destructiva, P. eupyrena Sacc., and P. arachidicola Marasas et al. he research on biotechnological exploitation of the fungus Phoma for the production of pharmaceutically active metabolites and for biological control of the weeds is gaining attention. he present paper reviews the production of secondary metabolites by diferent species of Phoma, their biotechnological application in antibiotic production and for biological control of weeds. Roles in biotechnology Various species of the genus Phoma produce numerous important secondary metabolites which includes phytotoxins, antimicrobials, and mycoherbicides some of which are highlighted in the following section. A. Phytotoxins Phoma lingam (Tode ex. Fr.) Desm Phoma lingam (Tode) Desm. is an asexual stage of the ascomycetous fungus Leptosphaeria maculans Ces. et de Not. It is the causative agent of blackleg or stem canker disease of several economically important cruciferous crops. Blackleg occurs worldwide and can be a particularly devastating disease for rape-seed and canola (Brassica napus and B. rapa) oil-seed crops (Kruse and Verreet 2005). his species produces two important phytotoxic compounds, i.e., sirodesmin PL and deacetylsirodesmin 183 PL (Ferezou et al. 1977). Phomamide (cyclo-O-(yydimethylallyl)-l-serine), a phytotoxic intermediate compound, has been extracted from this fungus during Sirodesmin synthesis (Curtis et al. 1977; Vining and Wright 1977; Ferezou et al. 1980a, 1980b; Stoessl 1981). Structure CH3 C O OO OH O CH3 H N O CH3 CH3 S S N O CH3 HO Figure 1. Structure of Sirodesmin PL. Biological activity Boudart (1989) evaluated antibacterial activity of sirodesmin PL (8) (Figure 1), a phytotoxin isolated from a highly virulent toxin producing isolate of P. lingam. he author reported that Gram positive bacteria (Staphylococcus aureus, Streptococcus faecalis, and Bacillus subtilis) were more susceptible to Sirodesmin PL compared to Gram negative bacteria (Salmonella typhi, Escherechia coli, Enterobacter cloacae, Proteus vulgaris, Shigella dysenteriae, Citrobacter freundii, Pseudomonas aeruginosa, Serratia liquefaciens, and Klebsiella pneumoniae). He further reported inhibition of RNA synthesis as a possible mechanism of sirodesmin PL toxicity. Pedras et al. (2000) studied the secondary metabolite proiles of 26 isolates of the blackleg fungus L. maculans. he blackleg pathogen is divided into several pathogenicity groups on the basis of phenotypic interaction (IP) of isolates on diferential cvs. Westar, Glacier, and Quinta. Isolates PG2, PG3, PG4, and PGT are highly virulent, but PG1, which has been named Leptosphaeria biglobosa Schomaker & H. Brun, is weakly virulent (Shoemaker and Brun 2001). hese secondary metabolites have also been used for diferentiation of Phoma backleg isolates. Based on HPLC analyses, 26 isolates can be placed in three main groups as follows: i. isolates producing Phomamide and Sirodesmins ii. isolates producing Indolyldioxopiperazines iii. isolates producing Polyketides 184 Mahendra Rai et al. his idea of classiication based on chemotaxonomy gives a new insight to the taxonomy of the Phoma isolates. Pedras et al. (2008) reported bioactive compounds from virulent strain of L. maculans grown in minimal liquid medium. hese compounds include mainly sirodesmins PL (1) (Pedras 2000), deacetylsirodesmin PL (2), and sirodesmins H (3), J (4), and K (5) and Phomamide (6) are co-produced metabolites in less quantity. Moreover, Phomalide (7) a host-selective toxin was also reported. In potato dextrose broth, L. maculans did not produce toxin. However, 2,4-dihydroxy-3,6dimethylbenzaldehyde (8) was isolated from PDB (Pedras et al. 2008) (Figure 2). Structure O 1 2 3 4 5 O RO HO N Sn N O H OH n=2, R=Ac n=2, R=H n=1, R=Ac n=3, R=Ac n=4, R=Ac O O O HN NH HN O HN HO 6 O O OO O O N H 7 Me CHO OH HO Moreover, other maculansin type structures and metabolite 2,4-dihydroxy-3,6-dimethylbenzaldehyde demonstrated remarkable inhibitory activity against root growth of brown mustard and canola (Pedras et al., 2008). Phoma herbarum Westend Brefeldin A (Figure 3), a component with pronounced phytotoxic property has been isolated from several fungi including P. herbarum (Table 1). It is a macrocyclic lactone with broad bioactivity like cytotoxic, antifungal, and antiviral. Betina (1992) reported that brefeldin A acts as an inhibitor of intracellular protein export with profound efects on the structure and function of the Golgi apparatus in animal cells (Cole et al., 2000). he authors reported efects on fungal growth and morphogenesis, inhibition of mitosis in plant cells, cytotoxicity, cancerostatic, antiviral, and antinematodal activity and peculiar efects on DNA, RNA, and protein synthesis in microbial and animal cells. Brefeldin A (BFA) has proved to be of great value as an inhibitor of protein traicking in the endomembrane system of mammalian cells (Sciaky et al. 1997). Culture iltrates of Phoma sorghina (Sacc.) Boerema, Dorenbosch, & van Kesteren caused necrosis when spotted on pokeweed leaves and eight other weed species, indicating a non-speciic nature (Venkatasubbaiah et al. 1992). BFA reduced radial growth in Pisolithus tinctorius at a concentration as low as 2 M. he ultrastructure in freeze-substituted hyphae showed that BFA treatment resulted in (i) disruption of the Spitzenkörper, (ii) reduction in number of apical vesicles, (iii) redistribution and mild dilation of ER, and (iv) persistence and increased size and complexity of Golgi bodies. CHO 8 Structure Figure 2. Production of metabolites by Leptosphaeria maculans: In minimal liquid medium (1–7) and potato dextrose broth (8). H In 2008, Pedras et al. isolated eight new stress inducing metabolites from L. maculans. hese include Leptomaculins and deacetyl-leptomaculins A–E. Leptomaculins A and B are the irst examples of naturally occurring 2-3-oxopiperazinethione and 2-3dioxopiperazine, respectively. he authors found stress inducing activity in the fungal phytotoxins sirodesmins PL and deacetylsirodesmin PL but not in any of the new Leptomaculins, Phomalide, or Phomamide. hey discovered maculansin A (9) and maculansin B (10). Pedras et al. (2008) carried out bioactivity assay and reported that maculansin A was more toxic to the resistant plant (Brassica juncea) than to the susceptible plant (Canola). OH O O HO CH3 Figure 3. Structure of Brefeldin A. Structure and synthetic pathways of the compound have been extensively discussed in many publications (Sigg 1964; Suzuki et al. 1970; Weber et al. 1971; Mabuni et al. 1979). Rivero-Cruz et al. (2000) found two new phytotoxic nonenolides, herbarumin I and herbarumin II, in extracts of Phoma herbarum (West.). hese compounds, each containing a 10-membered heterocyclic Phoma Saccardo: Distribution, secondary metabolite production and biotechnological applications Table 1. Phytotoxin metabolite secretion by Phoma species. Phytotoxic metabolite References Phomalide Pedras et al. 1993 Phomapyrone A Pedras et al. 1973, 1994 Phomamide and Sirodesmins Pedras 1996 l-Valyl-l-tryptophan anhydride Pedras et al. 1998 Phomalairdenone Pedras et al. 1999 3-nitro-1,2-benzene dicarboxylic acid Vikrant et al. 2006 (3 nitrophthalic acid) Glycoprotein (Pt60) Fogliano et al. 1998 185 Structure CH2 H 3C OH CH3 H OH H HN O O O Figure 4. Structure of Cytochalasine B-3. ring, caused signiicant inhibition of radicle growth of Amaranthus hypochondriacus. Biological activity Pandey et al. (2002) however also reported severe phytotoxicity of cell free culture filtrate obtained from P. herbarum FGCC#3 and 4 against Lantana camara. They recorded severe chlorosis, curling and finally complete collapse of leaves within 48 hours of treatment. Toxic metabolites produced by FGCC#3 are thermostable and thermotolerant. Compound isolated with benzene solvent showed maximum phytotoxicity. Vikrant (2002) and Vikrant et al. (2006) reported pronounced phytotoxicity of Cell Free Culture Filtrate of P. herbarum FGCC#75 against Parthenium hysterophorus, which is due to a chemical 3-nitro-1,2-benzenedicarboxylic acid (3-nitrophthalic acid). Phoma exigua Desm Phomenon is a highly phytotoxic eremophilane compound isolated from this fungus. Rothweiler and Tomm (1966, 1970) puriied and characterized the Phomin and Dehydrophomin from the culture iltrate of P. exigua Desm. var. exigua. Phytotoxicity of Phomin has been demonstrated. Other phytotoxic cytochalasins, viz., Deoxaphomin, Proxiphomin, Protophomin, p-hydroxybenzaldehyde and Cytochalasin A, B (Figure 4), have also been extracted from this pathogen (Rothweiler and Tomm 1966; Binder and Tamm 1973a, 1973b; Scott et al. 1975). More specifically, cytochalasin A, B, F, T, U, V, Ascochalasin, Deoxaphomin, and 7-O-Acetylcytochalasin B have been extracted from Phoma exigua var. heteromorpha (Schulzer & Sacc.) Noordel. & Boerema (Capasso et al. 1991a, 1991b; Evidente et al. 1992). Vurro et al. (1997) have extensively reviewed the technological and biological aspects of these compounds. Biological activity Diferent phytotoxins like Cytochalasins, Deoxaphomin, and p-hydroxybenzaldehyde produced by P. exigua were found to be efective herbicidal agents. he potential of these biocontrol agents have been studied by Cimmino et al. (2008), they reported the efect of these phytotoxins on the leaves of weed plants, viz., Cirsium arvense and Sonchus arvensis and found that p-hydroxybenzaldehyde was inactive, whereas deoxaphomin demonstrated the highest level of toxicity on leaves of S. arvensis. Cytochalasin appeared to be the less toxic in case of both the plants. Phoma sorghina (Sacc.) Boerema et al. he fungus incites a leaf-spot infection in pokeweed (Phytolacca americana L.) and other hosts. Several phytotoxins, viz., diphenyl ether, epoxydon, desoxyepoxydon, phyllostine, 6-methyl salicyalate ether have been produced by the pathogen. Among these, epoxydons have shown very high broad-spectrum toxicity to both mono- and dicot weed species (Venkatasubbaiah et al. 1992; Abbas and Duke 1997). Tenuazonic acid in the form of Mg and Ca chelates was also obtained from this species (Steyn and Rabie 1976) (Figure 5). Structure O HO CH3 H3C N H O CH3 Figure 5. Structure of Tenuazonic acid. Biological activity he efect of tenuazonic acid was studied on the growth and total Chl contents of Chlamydomonas reinhardtii. It 186 Mahendra Rai et al. was not signiicantly afected by toxin dosages at lower than 50 and 25 g/mL concentrations. However, with increasing tenuazonic acid concentrations, marked inhibition of the growth and chl contents was observed. Also the efect of this toxin was studied on proliferation of mammalian cells, at all treatment concentrations from 12.5 to 400 g/ mL, tenuazonic acid inhibited cell proliferation of the 3T3, CHL, and L-O2 cells occurs (Zhou and Qiang 2008). Phoma macdonaldii Boerema Phoma macdonaldii, the causal agent of the sunlower black stem disease, is responsible for qualitative and quantitative damage which can result in up to 60% yield losses. Structure CH3 C CH2OH CH2 CH2 O CH3 CH2OH CH3 OCH3 Figure 6. Structure of Zinniol. important plant only. It seems promising that Phoma and related species have potential as mycoherbicides. Summary Phoma lingam (asexual stage of the ascomycetous fungus Leptosphaeria maculans) is one of the highly studied Phoma species which produced many phytotoxins like sirodesmin PL, deacetylsirodesmin PL, Leptomaculins and its derivatives (i.e., Leptomaculins A–E). hese phytotoxins produced have same biological role (antimicrobial potentials) but chemically they have some diferences in their structures. Brefeldin A is another phytotoxin produced by P. herbarum which also have antifungal and antiviral activities and also acts as a inhibitor of intracellular protein export with profound efects on the structure and function of the Golgi apparatus in animal cells. P. exigua produces mainly Phomenon and other phytotoxic Cytochalasins, viz., Deoxaphomin, Proxiphomin, Protophomin, A B C D Biological activity Zinniol (Figure 6) is a phytotoxin extracted from this pathogen that is responsible for leaf and stem blight and withering of cut seedlings of many plants (Sugawara and Strobel 1986). his toxin binds to speciic binding sites and is associated with stimulation of Ca2+ uptake by the afected cells at only 0.1–1.0 m levels. Calciumregulated cell processes may be disrupted by this toxin. Its relatively simple in structure and could be the basis for discovery of herbicide (Abbas and Duke 1997). Phoma foveata Foister his fungus causes lesions on potato tubers (Solanum tuberosum) in Europe known as gangrene (Figure 7), formerly treated as a pigment producing variety of the ubiquitous P. exigua var. exigua, which may also cause gangrene-like lesions on potatoes. Pachybasin (Figure 8), a phytotoxin extracted from P. foveata by Strange (1997), may represent one component of this toxicity. Biological activity It is evident that Phoma spp. could be novel agents for biocontrol of many weeds. hey have both mycoherbicidal and biorational properties. Looking to the number of known species, species associated with weeds are very few. his might be because of ignorance of weed pathogens. In the past, mycologists and plant pathologists have paid attention to the diseases of economically Figure 7. Phoma foveata causes gangrene on potato tubers: (A) Symptom on tuber; (B) 2 weeks old colony on malt-agar; (C) reverse with pycnidia; (D) conidia. (Bar 10 m). Structure O OH CH3 O Figure 8. Structure of Pachybasin. Phoma Saccardo: Distribution, secondary metabolite production and biotechnological applications p-hydroxybenzaldehyde, and Cytochalasin A, B, these are active against some weeds like C. arvense and S. arvensis. Tenuazonic acid is produced by P. sorghina showed the herbicidal activity. he toxins produced by P. exigua and P. sorghina are biologically similar and showed the same herbicidal activities. P. macdonaldii produced phytotoxin zinnoil acts as efective herbicides. While pachybasin produced by P. foveata is active against some important weeds. 187 Structure HO OH O OH OH Me Me OH Me CH2OH Me Me A OH HO OH Production of crystals Certain Phoma and Ascochyta species produce very characteristic dendritic crystals growing under standard culture conditions. he chemical nature of these crystals has proved to be a speciic character especially useful in characterizing the pathogenic behavior and taxonomic delimitation of the taxa (Noordeloos et al. 1993). Within the large genus Phoma, species diferentiation in many cases is only possible using information obtained from cultures of these fungi on artiicial media (Aa et al. 1990). P. andina (=P. andigena Turkenst. apud Boerema et al.) and P. chrystalliniformis (Loer. et al.) Noordel. & Gruyter were originally considered as varieties of the same species. P. crystalliniformis and P. medicaginis Malbr. & Roum. produce Brefeldin A, as P. andigena produces Radicinin. he most common metabolites are Pinodellalide A and Pinodellalide B both produced by P. arachidicola, P. pinodella, P. dorenboschii Noordel. & Gruyter, and Ascochyta pinodes L.K. Jones (Noordeloos et al. 1993). Some Phoma spp. produce luorescent secondary metabolites as well (Boerema and Loerakker 1985). O O Me OH Me Me CH2OH Me Me OH B Figure 9. (a) Phomenoic acid, (b) Phomenolactone, Me = Methyl group. Structure 24 O OH 22 20 OH 12 13 O 19 H 3 6 O 7 14 9 H H 1 N H O 16 18 Figure 10. Structure of antimicrobial compound YM-215343 (1). B. Antimicrobials lingam exhibited antifungal activity particularly against Candida albicans (Devys et al. 1984, 1986) Phoma species also produce several important antimicrobial compounds (Pearce 1997; Singh et al. 1997; Baxter et al. 1998). Phoma betae Phoma lingam Topgi et al. (1987) isolated phomenoic acid and phomenolactone from P. lingam to understand the mechanism of biosynthesis of these compounds. he authors stated that the results do not allow them to predict the biochemical role of such substances in the cells responsible for their synthesis. Biological activity Phomenoic acid (Figure 9a) and Phomenolactone (Figure 9b) isolated from the mycelium of P. P. betae is known to produce bioactive diterpenes (Ichihara et al. 1984; Oikawa et al. 2001) including aphidicolin (Lin et al. 2003). Shibazaki et al. (2004) reported a bioactive compound from YM-215343 (1) from the crude culture extract of a strain of Phoma QNO4621 (Figure 10). Biological activity he compound exhibited antifungal activity against human pathogenic fungi—Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus (MIC values 2–16 µg/mL). In addition, it also demonstrated cytotoxicity against HeLa S3 cells with an IC50 of 3.4 µg/mL. 188 Mahendra Rai et al. Structure H H C C C OH CO2H Phomallenic acid A H H CO2H C C C Phomallenic acid B H H CO2H C C C eicacy (MIC 250 g/mL) compared to others but its activity was comparable to thiolactomycin. he better eicacy was shown by Phomallenic acid B (2) and C (3) and demonstrated MIC values of 12.5 and 3.9 g/mL against wild-type strains of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Encouragingly, their antibacterial activity was 5–32-fold higher than thiolactomycin. However, Phomallenic acid (A–C) (Figure 8) did not exhibit any activity against both Gram positive and Gram negative bacteria, viz., Enterococcus faecalis, E. faecium, and E. coli. Phomallenic acid C Figure 11. Structure of Phomallenic acid A, B, C. Phoma sp It produces an important secondary metabolite Phomallenic acid (A–C) which have antimicrobial potential. Biological activity Ondeyka et al. (2006) evaluated antimicrobial activity of Phomallenic acid (A–C) isolated from Phoma sp. and compared with thiolactomycin. he authors reported that Phomallenic acid A (1) (Figure 11) showed the least Some other metabolites produced from diferent Phoma species he pharmaceutically active metabolites Squalestatin-1 (S1) and Squalestatin-2 (S2) are produced by a Phoma sp. (IMI 332962) (Baxter et al. 1998). Singh et al. (1997) reported production of some antitumor agents by Phoma sp. (MF 6118). hese include Fusidienol-A, which is the second member of the Fusidienol family of inhibitors to possess a novel tricyclic oxygen-containing heterocycle with a 7/6/6 ring system. Equisetin and Phomasetin obtained from species of Phoma are useful against AIDS (Singh et al. 1998). Singh et al. (1998) isolated equisetin derived from Phoma sp. (MF 6070). his showed Table 2. Bioactive compounds produced by diferent species of Phoma. Phoma sp. Bioactive compounds/ derivatives P. exigua var. exigua Antibiotic E (antibacterial and antifungal) Cytochalasin B P. lingam asexual state of Phomenoic acid and phomenolactone Leptosphaeria maculans (antifungal and antibacterial) Sirodesmin PL Marine P. sp. Phomactin A P. exigua var. heteromorpha Cytochalasin F Phoma sp. Squalestatin (antiinfective agents) Phoma sp. Phoma sp. Phoma sp. Phoma sp. Phoma sp. Phoma sp. Phoma sp. Phoma sp. (NRRI 25697) Phoma sp. Phoma sp. P. herbarum Phoma sp. QNO4621 Phoma sp. (FKI-1840) P. sorghina Phoma sp. Phoma sp. (SANK 13899) Phoma sp. (No. 00144) Phoma sp. Squalestatin 1, 2 (S1, S2) Antiviral agent (against HIV) Equisetin Antiviral agent (against HIV) Equisetin and Phomasetin Antitumour(Fusidienol A) Antibiotic, antitumour, RKS-1778 Pesticide (Octahydronaphthol derivative MK8383, patent) Antibiotic activities antibacterial (Phomadecalins A-D) Antifungal (YM-202204) FOM-8108, inhibitors of neutral sphingomyelinase Herbicide (Herbarumins I,II,III) Antifungal (YM-215343) Spylidone Novel athraquinone derivatives Antimicrobial (Phomallenic acid (A–C) Pleofungins Gluconeogenesis inhibitor FR225654 Antimicrobial (Pyrenophorol derivatives) References Boerema and Höweler 1967 Devys et al. 1984, 1986; Boudart, 1989 Sugano et al. 1991 Capasso et al. 1991 Dawson et al. 1992; Sidebottom et al. 1992; Pearce 1997 Baxter et al. 1992 Hazuda et al. 1999 Singh et al. 1998 Singh et al. 1997 Kakeya et al. 1997 Wakui et al. 1999 Sponga et al. 1999 Che et al. 2001 Nagai et al. 2002 Yamaguchi et al. 2002 Rivera-cruz et al. 2003 Shibazaki et al. 2004 Koyama et al. 2005 Warley and Pupo 2006 Ondeyka et al. 2006 Yano et al. 2007 Ohtsu et al. 2005 Zhang et al. 2008 Phoma Saccardo: Distribution, secondary metabolite production and biotechnological applications HIV virus integrase inhibition. Marine Phoma are also reported to possess antibiotic activities (Sponga et al. 1999). he marine species of Phoma showed antimycotic activities against Enterococcus faecium, Escherichia coli, and Candida albicans. Phoma species also produce certain other useful compound like the gluconeogenesis inhibitor FR225654 from Phoma sp. No. 00144 (Ohtsu et al. 2005); and Spylidone, a novel inhibitor of lipid accumulation in mouse (Koyama et al. 2005), and Pleofungins, inhibitor of inositol phosphorylceramide synthase, from Phoma sp. SANK 13899 (Yano et al. 2007) (Table 2). Recently, an endophytic Phoma betae was isolated from Smallanthus sonchifolius (Asteraceae family) by Gallo et al. (2008). he authors evaluated the eicacy of the extract of Phoma sp. against three cancer cell lines and reported that the compound present in extract was very active. Usually bioactive diterpenes including aphidicolin, which are speciic inhibitor of DNA polymerase are present in extract. he important group of secondary metabolites known as macrodiolides are known to occur in various fungi including Phoma sp. isolated from marine sponges. Such fungi have shown remarkable biological activity (Zhang et al. 2008). Due to broad spectrum biological activity and the unique structure, Pyrenophorol (kind of macrodiolides) has become a Structure 8′฀ 7′฀ O 1 O thurst area of research. Recently, Professor Krohn and his colleagues at the Department Chemie, Universität Paderborn (Warburger Str. 100, 33098 Paderborn, Germany) have been investigating the endophytic fungi to search for bioactive compounds. Krohn et al. (2007) and Zhang et al. (2008) isolated tetrahydropyrenophoral from Phoma sp. occured on Fagonai cretica plant. Tetrahydropyrenophoral is a hydrogenated pyrenophoral derivative. Further, Zhang et al. (2008) isolated another endophytic Phoma sp. (strain No. 8874) from the leaves of Lycium intricatum. his plant is a mediterranean and native to island Gomera of Spain. he authors reported pyrenophorol (1) and (−)-dihydropyrenophorin (3) together with four new analogues (2,4–6) and three novel ring-opened derivatives (7–9) (Figure 12). Biological activity of these compounds was evaluated against various microbes and remarkable antimicrobial activity was recorded against Microbotryum violaceum, Cholerella fusca, Escherechia coli, and Bacillus megaterium. Summary P. lingam is an important fungus which produced both phytotoxins as well as some important antimicrobial compounds which includes phomenoic acid and O O 8′฀ 7′฀ O 1 O 3 O OR 4′฀ HO 4′฀ O O O O 8 R = H: pyrenophorol (1) R = H: pyrenophorol (3) 2: R = AC 4: R = AC 7′฀ O 1 7 1′฀ O 7 O 8′฀ 3 HO O RO 1′฀ 8 5 O 8′฀ 7′฀ OR 7′฀ OH OH O O 1 1 3 4′฀ 4′฀ HO 7 1′฀ O 6 O O O 1′฀ O 7 8 O 4′฀ 4 HO O 189 4 HO O 1′ 7 8 O 8 7: R = H 8: R = AC 9 Figure 12. Structure of bioactive compounds (1–9) isolated from endophyte Phoma associated with Lycium intricatum. 190 Mahendra Rai et al. phomenolactone, while P. betae produced diterpenes, aphidicolin and a bioactive compound YM-215343. Above all the compounds produced by both P. lingam and P. betae have biologically similar role that these compounds showed efective antifungal activity against different ingi like Cryptococcus neoformans and Aspergillus fumigatus while these are potentially active against Candida albicans. On the other hand, Phomallenic acid (A–C) produced by Phoma sp. showed the antibacterial activity against wild-type strains of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). While some other compounds produced by diferent Phoma species have diferent biological role, i.e., gluconeogenesis inhibitor, antitumor agents, inhibitor of inositol phosphorylceramide synthase, etc. C. Herbicides Weeds are serious problems not only for the agricultural and forestry ields, but also to human and animal health. Synthetic chemical herbicides have been the mainstay for weed control from the end of World War II, and are no doubt responsible for much of the unparalleled increased crop productivity that has occurred during this period. he high costs included the developing and registering of chemical herbicides and recent trends in environmental awareness have prompted researchers to investigate alternative systems of weed control. Ideally, such a system would control target weeds at or near the same levels as that achieved with chemical herbicides while at the same time not posing a threat to either the environment or non-target organisms (Pandey et al. 2001). he science and technology of weed control using plant pathogensis as alternatives to chemical herbicides has recently gained signiicant attention and momentum. With advances in knowledge, biorational and integrated management strategies have also came into foray. Biological, technological, and economically perspectives of various strategies have been extensively reviewed in several publications (Hoagland 1990, 1999, 2001; Hasija et al. 1994; Abbas and Duke 1995, 1997; Boyette and Abbas 1995; Charudattan 1996; Deshmukh et al. 2006; Pandey et al. 1996a, 1996b, 1997, 2001; Pandey 1999, 2000; Saxena and Pandey 2000, 2001). Several species of the genus Phoma live parasitically or saprophytically on plants and are often associated with distinct disease symptoms, viz., leaf-spots, (Pathak and Chauhan, 1976; Khanna and Chandra, 1977) lesions on stem, fruits, or even on roots (tubers) (Padmbai, 1976), damping-of, die-back, seed and fruit rots, and seedling blight. It is surprising therefore that, despite excellent phytopathogenic potential shown by various species or varieties of the genus, their mycoherbicidal potential has been ignored signiicantly. Indeed, only a few attempts to evaluate them as mycoherbicides have been reported. Heiny (1990, 1994) isolated a highly host speciic strain of Phoma proboscis Heiny from diseased parts of ield bindweed (Convolvulus arvensis). Heiny and Templeton (1991) have reported very high mycoherbicidal activity when the agent applied to the seedling of the weed and atmospheric temperature ranged from 16°C to 28°C and more than 9 h dew period. Heiny (1994) extensively evaluated the compatibility of synthetic herbicides for integration with mycoherbicidal agents. Rajak et al. (1990) isolated a strain of P. herbarum Westend. from diseased leaves of Parthenium hysterophorus L. from Central India. he fungus, when applied 2.3 × 102 spores/mL, caused more than 90% inhibition in seed germination, seedling mortality, and leaf damage followed by reduction in height of the weed Parthenium (Pandey et al. 1991). Pandey and Pandey (2000) similarly recovered three strains of P. herbarum (LC#32, 37, 39) from diseased leaves and stem of Lantana camara, another problematic weed of India. All the three strains incite severe infection in the weed, especially at the seedling stage ( Pandey 2000). Pandey (2002) also isolated a strain of P. herbarum FGCC#70 from diseased seedlings of an invasive weed, Hyptis suaveolens (L.) Poit. She recorded very high mycoherbicidal potential when seedlings were treated at the rate of 2.0 × 105 spores/mL at 28 ± 1°C, 24 h dew period. Pandey (2000) evaluated the mycoherbicidal potential of indigenous fungal pathogens against Lantana camara L., an obnoxious weed of India. He isolated about 40 fungi from diferent parts of Madhya Pradesh. Out of these isolates, the maximum eicacy was shown by Alternaria alternata (Fr.:Fr.) Keissl. followed by P. multirostrata (P.N. Mathur et al.) Dorenb. & Boerema var. multirostrata. he later is thermophilic and originally reported from India by Mathur and hirumalachar (1959). It is widely distributed in subtropical and tropical regions and warm greenhouses. Zhou et al. (2004) demonstrated the bioherbicidal activity of P. macrostoma Mont. (var. macrostoma) against dandelion seedlings. P. macrostoma was also found to be efective in biological weed control (Bailey and Derby 2001; Zhou et al. 2005). Excellent pesticidal activity against some phytopathogenic fungi was reported in octahydronaphthol derivative MK8383 of a Phoma sp. (Wakui et al. 1999). Club root of cruciferous plants can be controlled by P. glomerata and its product epoxydon (Arie et al. 1998, Padmbai, 1976,1999). Sullivan et al. (2000) reported that P. glomerata has ability to colonize and inally inhibit the growth of powdery mildew on oak and thus can be used as a biocontrol agent. In fact, powdery mildews are common plant pathogens, which can be easily Phoma Saccardo: Distribution, secondary metabolite production and biotechnological applications identiied by formation of profuse white powder-like conidia and mycelia. For biological control of powdery mildews, only one fungus Ampelomyces quisqualis Ces. is known. herefore, enormous opportunities and possibilities are there to utilize this mycoparasitic fungus as a potential biocontrol agent. Summary Some species of Phoma are found to be associated with important weeds which are hazardous to the crop plants. hese species produces diferent toxins during their growth on these weeds which have mycoherbicidal potentials. Among these species Phoma proboscis is found to be efective against Convolvulus arvensis. P. herbarum Westend. from diseased leaves of Parthenium hysterophorus showed 90% inhibition in its seed germination. P. macrostoma was also found to be efective in biological weed control. Looking into the herbicidal potential, some Phoma species can be utilized for biological control of weeds. Production of anthraquinones here are many fungi including Phoma, which produce anthraquinones as secondary metabolite. Fungal anthraquinones as polyketide-derived secondary metabolites occur widely in many genera of fungi. Compared with the commercially available hydroxyanthraquinones, most possess an additional methyl substitution in position three, e.g., Emodin and this allows a study of the efect of such a group on the dyeing properties of dyestufs derived from them. A fungal anthraquinone Cynodontin (1,4,5,8-tetra hydroxy3-methylanthraquinone) was produced in suicient purity to allow it to be transformed using a simple chemical step to a dye product and this was compared with a commercially available close analogue (Hobson et al. 1997). Bick and Rhee (1966) reported that P. exigua var. foveata (=P. foveata) contains many anthraquinone pigments, such as Pachybasin, Chrysophanol, Emodin, and Phomarin. In acid condition, this complex of pigments become yellow and in alkaline conditions red. his character is based on ammonia test described by Logan and Khan (1969). On malt-agar, P. foveata gives pinkish color after exposure to ammonia. his is due to reaction of diffusible anthraquinones and their reaction with ammonia. In old cultures, anthraquinone pigments crystallize out as yellow-green crystals. Tichelaar (1974) found that the fungicide thiophanate-methyl accelerates and increases the crystallization process of the pigments. Both P. exigua var. exigua and P. exigua var. inoxydabilis 191 (=P. exigua var. heteromorpha) produce Cytochalasin B, which are also known as “Phomine” (Bousquet and Barbier 1972; Scott et al. 1975). Some isolates of P. exigua var. foveata (=P. foveata) produce antibiotic substance (‘E metabolite’) similar to isolates of the ubiquitous P. exigua var. exigua (Boerema and Höweler 1967). It is a colorless substance and can easily be demonstrated in cultures by the sodium hydroxide test. On application of a drop of 0.1% NaOH at the margin of colonies on malt agar, oxidation (Boerema and Höweler 1967) takes place and pigment alpha converts into pigment beta. Pigment alpha is red-purple at pH < 10.5 and blue-green at pH > 12.5. Pigment beta is yellow at pH < 3.5 and red at pH > 5.5. Anthraquinone pigments are also produced by some other Phoma species. Some other species of Phoma also produce anthraquinones and Phomalgin A (Birch et al. 1964; Pedras et al. 1995). he potential of these pigments can be utilized commercially. Chiba et al. (2006) reported that the fungus P. herbarum produces magenta pigment. Phoma sorghina is known for anthraquinone production (Figure 13). Borges and Pupo (2006) reported the production of four anthraquinones derivatives: Compound 1 (1,7-dihydroxy-3-methyl9,10-anthraquinone), compound 2 (Phomarin, 1,6dihydroxy-3-methyl-9,10-anthraquinone), compound 3 (Pachybasin,1-hydroxy-3-methyl-9,10-anthraquinone), and compound 4 (1-7-dihydroxy-3-hydroxymethyl-9,10anthraquinone) and two new hydraquinone derivatives from an endophyte P. sorghina isolated from Tithonia diversifolia, an important plant of family with high medicinal value (Figure 14). A B C D Figure 13. (A) and (B) In vitro production of anthraquinone pigments by Phoma sorghina. (C) and (D) Antibacterial activity of anthraquinone produced by P. sorghina. 192 Mahendra Rai et al. Structure OH O O O OH OH HO HO O O O 1 2 3 O HO 8a OH OH OH 9a 4a 5a OH HO 3 5 OH H 1 7 OH H OH 11 HO H O O 4 5 H O 6 Figure 14. Phoma sorghina: Anthraquinone derivatives isolated from rice culture medium. he chemical synthesis of anthraquinones require the use of strong acids at high temperature and heavy metal catalysts, as a consequence of which environmentally hazardous eluents and byproducts are produced. With increasing awareness of the environment degradation by industry, the disposal of industrial eluent is becoming more costly and strictly regulated. Now the anthraquinone producing fungi can be cultivated in bioreactors, which has emerged as a highly promising alternative for the commercial production of anthraquinones. hus, there is vast scope for commercial exploitation of anthraquinone producing species of Phoma. Conclusion he application of microbial secondary metabolites in various ields of biotechnology has attracted the interests of a broad array of researchers. Phoma species are a rich but under-recognized source of such metabolites. Screening of diferent species of Phoma to address the diverse range of unmet medical needs thus represents a potentially fruitful idea, which may open up new vistas in the ield of secondary metabolite production. Acknowledgments he authors would like to thank Dr Sheo Singh, Merck Research Laboratories, New Jersey; Dr. M. S. C. Pedras, Canada Research Chair in Bioorganic and Agricultural Chemistry, University of Saskatchewan, SASKATOON, Canada; Dr. Barbara Schulz, Institut fuer Mikrobiologie Technische Universitaet Braunschweig, Germany; Dr. Masatoshi Taniguchi, Astellas Pharma Inc., Japan; Dr. Monica Tallarico, Pupo, Brazil, Prof. Dr. h.c. K. Krohn, Department Chemie, Universität Paderborn, Warburger Str., Germany, for suggestions and supply of literature. Declaration of interest: he authors report no conlicts of interest. he authors alone are responsible for the content and writing of the paper. 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