Abstract
Mycoparasitic fungi, fungi preying on other fungal species, are prolific producers of volatile and non-volatile secondary metabolites. Several secondary metabolites are produced during mycoparasitism to weaken the host and support attack and parasitism. Further, evidence accumulated that some secondary metabolites also act as communication molecules. Besides their antagonistic activity, several fungal mycoparasites exhibit beneficial effects on plants and some of their secondary metabolites have plant growth-promoting and defense stimulating activities. As many secondary metabolism-associated gene clusters remain silent under standard laboratory conditions, the full variety as well as the underlying biosynthetic pathways employed by fungal mycoparasites for secondary metabolite production still await clarification. Nonetheless, the variety of currently known secondary metabolites and their range of activities is impressive already and they exhibit a great potential for agriculture, pharmacology and other industrial applications.
Keywords
- secondary metabolites
- volatile organic compounds (VOCs)
- peptaibiotics
- mycoparasitism
- biocontrol
1. Introduction
Mycoparasitic relationships, where a predatory fungal species gains nutrients on the expense of a host fungus, are widespread within the fungal kingdom. By the modalities of this non-mutual relationship, biotrophic and necrotrophic mycoparasitic fungi with different gradations within this classification (contact, invasive or intracellular necrotrophic; haustorial or fusion biotrophic) can be distinguished [1]. Biotrophic mycoparasites co-exist and nourish on their living host in a balanced way and are specifically adapted to one or few host species. In contrast, necrotrophic fungi destructively invade and kill a broad range of hosts to gain nutrients from the remains of their prey [2]. Mycoparasitic fungi are prolific producers of a plethora of volatile and non-volatile secondary metabolites, favoring their ecological fitness and survival under certain environmental conditions. For example, the excretion of siderophores – affecting high affinity iron chelation – is strongly up-regulated under iron-limiting conditions [3] and several antimicrobial metabolites empower the successful perseverance within the ecological niche [4]. The mycoparasitic lifestyle obviously substantiates the overrepresentation of secondary metabolism-associated genes and the extensive excretion of a variety of secondary metabolites [2] enabling the fungus´ successful access to its prey as well as its thriving persistence in or assassination of the host. Furthermore, selected fungal secondary metabolites are known to exhibit beneficial effects on plants: They may promote vitality and growth of roots and shoots, enhance the resilience against abiotic stress factors and prime the plants immune system (induced systemic resistance; ISR) thereby enhancing its resistance and survival in case of prospective infections with pathogens [5]. In recent times, evidence accumulated that some secondary metabolites also act as communication molecules over species boundaries [6, 7].
A great diversity of mycoparasitic species exists in the fungal kingdom, especially within the order
A characteristic trait of filamentous fungi is that their secondary metabolism-associated genes are mostly situated within subtelomeric regions of the chromosomes in large biosynthetic gene clusters present in the genomes in significantly greater numbers than secondary metabolites currently identified [19]. The unique and often uncommon biosynthetic pathways are mostly characterized by signature enzymes, often also transcription factors and transporters present in the respective gene clusters, which enable the secondary metabolite synthesis starting from simple precursors gained from primary metabolism like amino acids and acetyl-CoA [20]. Most common core enzymes are non-ribosomal peptide synthases (NRPSs), polyketide synthases (PKSs) and terpene-synthases or -cyclases [4]. In necrotrophic mycoparasitic species like
2. Non-ribosomal peptides
Non-ribosomal peptides (NRPs) are synthesized by NRPSs, enzymes that characteristically consist of multiple domains synthesizing the peptide in one by one steps. Characteristic for NRPSs are the core domains for adenylation, thiolation and condensation. The generated NRPs are very diverse: they mostly comprise of proteinogenic and non-proteinogenic amino acids, can be linear or branched to cyclic with a varying length. After their synthesis outside of the ribosome, they frequently pass extensive secondary modifications. Many fungal NRPs have high economic and/or ecologic value like β-lactam antibiotics, the immunosuppressant cyclosporine A but also mycotoxins like gliotoxin.
The occurrence of NRPS genes is enriched within the genome of mycoparasitic
2.1. Peptaibiotics
Peptaibiotics are mostly linear to rarely cyclic polypeptides, with a size of 0.5–2.1 kDa consisting of 4–21 residues. Characteristic for peptaibiotics is the inclusion of the non-proteinogenic amino acid α-aminobutyric acid (Aib). By module-skipping one NRPS is frequently capable of synthesizing a whole set of peptaibiotics [23, 24]. According to their sequence alignment and structure, peptaibiotics can be divided into several sub-clades: peptaibols, lipopeptaibols, lipoaminopeptides, cyclic peptaibiotics and two very special, small categories [25]. Because of their unusual synthesis and appearance, they are not included in regular protein databases, but in the “Comprehensive Peptaibiotics Database” [25].
Peptaibols are solely described for filamentous fungi exhibiting a mycoparasitic lifestyle, with a high abundance of over 80% of all known substances being derived from
Whereas all
2.2. Epipolythiodioxypiperazines
Epipolythiodioxypiperazines (ETPs) are characterized by the presence of an inter- or intramolecular disulfide bridge and a diketopiperazine core. The toxicity of ETPs lies in the disulfide bridging which is facilitating the inactivation of proteins by conjugation and the elicitation of reactive oxygen species (ROS) [36]. The best known substance of this class is gliotoxin derived from
The weak mycoparasitic
2.3. Siderophores
Siderophores of fungal origin are high affinity iron chelating, linear to cylic oligomeric secondary metabolites mostly characterized by a N5-acyl-N5-hydroxyornithine basic unit [3]. Several siderophores are derived by one NRPS and post-synthetic subsequent modification [43]. As bio-available iron is rare in natural habitats, but an essential trace element to most organisms, efficient chelation, uptake and storage mechanisms for iron play an important role in competition and perseverance, especially within dense microbial communities like in soil [44]. Siderophores are important metabolites in the response against oxidative stress in several fungi like
Evidences accumulate that siderophores act in biocontrol as virulence factors against other microbes during iron competition. Further, they promote plant growth by the reduction of oxidative stress: in biocontrol of
3. Polyketides (PKs)
Polyketides (PKs) are derived from simple building blocks like acetyl-CoA or malonyl-CoA via consecutive PKS-mediated decarboxylative condensation and subsequent post-synthetic modification. Fungal PKSs are complex multi-modular enzymes, which obligatory include a characteristic ketoacyl-CoA-synthase (KS), an acyltransferase (AT) and an acyl-carrier (ACP) domain [20]. The structurally diverse PKs are the main class of secondary metabolites derived from fungi. The spectrum of substances ranges from spore pigments over antibiotics to toxins [2].
The
4. Terpenoids
Terpenoids are synthetized from the acetyl CoA-derived C-5-isopentenyl-diphosphate intermediates isopentenyl- and dimethylallyl-diphosphate. The C-5 units are subsequently processed via head-to-tail condensation by prenyl synthases and are post-synthetically modified by various enzymes resulting in different terpenoids originating from very few C-5 precursors [56]. Terpenoid biosynthetic clusters are characterized by the presence of a terpene cyclase gene [4]. Terpenoids are volatile to non-volatile substances constituting the highest abundant natural products on earth [37]. Terpenoids of fungal origin comprise phytohormones, mycotoxins as well as antibiotics and antitumor substances.
The
5. Ecology and regulation of secondary metabolism in mycoparasitic fungi
Ancestral and recent lifestyles fundamentally influence the existence as well as the expression of secondary metabolite genes and clusters up to the species or even strain level. The transcriptional responses of
Several environmental cues like temperature, light, carbon, nitrogen, pH and competing or synergistic organisms are known to influence the transcriptional regulation of secondary metabolism-associated gene clusters (Figure 1). Suboptimal environmental conditions thereby often facilitate and promote transcriptional activation or transcriptional reprogramming events [70]. In media containing chitin or
Like known for the production of mycotoxins in non-mycoparasitic species [73], secondary metabolite production in mycoparasitic fungi is governed by heterotrimeric G protein signaling and the associated cAMP-pathway, as well as mitogen-activated protein kinase (MAPK) cascades [74, 75].
6. Cross-talk by and response to secondary metabolites in mycoparasitic interactions
In bacteria, it has been shown that at sub-inhibitory concentrations antibiotics serve as mediators of microbial communication and interaction with one of the outcomes being the production of cryptic metabolites [81]. Accordingly, the interaction with other fungi may shape the secondary metabolite profile of a specific fungus, making co-cultures a valuable tool for eliciting the activation of silent secondary metabolism-associated gene clusters.
Studies on the mutual effects of secondary metabolites produced during mycoparasitic interactions are rare however.
Co-culturing of mycoparasites with prey fungi simulates the conditions occurring during the mycoparasitic interaction in natural or agricultural systems and could hence encourage the production of secondary metabolites via communication and signaling molecules. Accordingly, pairwise interactions of
Based on these studies, it is evident that secondary metabolites contribute to mycoparasitic interactions in various ways including inhibition of the activity or synthesis of mycoparasitism-relevant enzymes and other substances, by eliciting defense and detoxification responses or by triggering the production of cryptic metabolites. In most cases, however, information on the spatial distribution of the secreted substances is lacking and it is hence difficult to assign novel secondary metabolites specifically induced during the co-cultivation to its actual producer. Recently, mass spectrometry-based imaging (MSI) turned out as a valuable tool for in situ visualizing the dynamics and localization of small molecules released during microbial interactions [94]; however, reports on its application to mycoparasitic fungus-fungus interactions are still rare. By applying matrix-assisted laser desorption/ionization (MALDI)-based MSI for visualization and identification of secondary metabolites being exchanged during the mycoparasitic interaction of
Acknowledgments
We acknowledge support by the Austrian Science Fund FWF (grant P28248) and the Vienna Science and Technology Fund WWTF (grants LS09-036 and LS13-086).
References
- 1.
Jeffries P. Biology and ecology of mycoparasitism. Canadian Journal of Botany. 1995; 73 (S1):1284-1290. DOI: 10.1139/b95-389 - 2.
Karlsson M, Atanasova L, Jensen DF, Zeilinger S. Necrotrophic mycoparasites and their genomes. Microbiology Spectrum. 2017; 5 :FUNK-0016-2016. DOI: 10.1128/microbiolspec.FUNK-0016-2016 - 3.
Renshaw JC, Robson GD, Trinci APJ, Wiebe MG, Livens FR, Collison D, Taylor RJ. Fungal siderophores: Structures, functions and applications. Mycological Research. 2002; 106 :1123-1142. DOI: 10.1017/S0953756202006548 - 4.
Mukherjee PK, Horwitz BA, Kenerley CM. Secondary metabolism in Trichoderma – A genomic perspective. Microbiology. 2012;158 :35-45. DOI: 10.1099/mic.0.053629-0 - 5.
O’Brien PA. Biological control of plant diseases. Australasian Plant Pathology. 2017; 46 :293-304. DOI: 10.1007/s13313-017-0481-4 - 6.
Fischer GJ, Keller NP. Production of cross-kingdom oxylipins by pathogenic fungi: An update on their role in development and pathogenicity. Journal of Microbiology. 2016; 54 :254-264. DOI: 10.1007/s12275-016-5620-z - 7.
Vinale F, Sivasithamparam K, Ghisalberti EL, Marra R, Barbetti MJ, Li H, Woo SL, Lorito M. A novel role for Trichoderma secondary metabolites in the interactions with plants. Physiological and Molecular Plant Pathology. 2008;72 :80-86. DOI: 10.1016/j.pmpp.2008.05.005 - 8.
Viterbo A, Inbar J, Hadar Y, Chet I. Plant disease biocontrol and induced resistance via fungal Mycoparasites. In: Kubicek CP, Druzhinina IS, editors. Environmental and Microbial Relationships: The Mycota. Vol. 4. Berlin, Heidelberg: Springer; 2007. pp. 127-146. DOI: 10.1007/978-3-540-71840-6_8 - 9.
Schmoll M, Dattenböck C, Carreras-Villaseñor N, Mendoza-Mendoza A, Tisch D, Alemán MI, Baker SE, Brown C, Cervantes-Badillo MG, Cetz-Chel J, Cristobal-Mondragon GR, Delaye L, Esquivel-Naranjo EU, Frischmann A, Gallardo-Negrete JJ, García-Esquivel M, Gomez-Rodriguez EY, Greenwood DR, Hernández-Oñate M, Kruszewska JS, Lawry R, Mora-Montes HM, Muñoz-Centeno T, Nieto-Jacobo MF, Nogueira Lopez G, Olmedo-Monfil V, Osorio-Concepcion M, Piłsyk S, Pomraning KR, Rodriguez-Iglesias A, Rosales-Saavedra MT, Sánchez-Arreguín JA, Seidl-Seiboth V, Stewart A, Uresti-Rivera EE, Wang C-L, Wang T-F, Zeilinger S, Casas-Flores S, Herrera-Estrella A. The genomes of three uneven siblings: Footprints of the lifestyles of three Trichoderma species. Microbiology and Molecular Biology Reviews. 2016;80 :205-327. DOI: 10.1128/MMBR.00040-15 - 10.
Mukherjee PK, Horwitz BA, Herrera-Estrella A, Schmoll M, Kenerley CM. Trichoderma research in the genome era. Annual Review of Phytopathology. 2013;51 :105-129. DOI: 10.1146/annurev-phyto-082712-102353 - 11.
Quandt CA, Bushley KE, Spatafora JW. The genome of the truffle-parasite Tolypocladium ophioglossoides and the evolution of antifungal peptaibiotics. BMC Genomics. 2015;16 :553. DOI: 10.1186/s12864-015-1777-9 - 12.
Quandt CA, Di Y, Elser J, Jaiswal P, Spatafora JW. Differential expression of genes involved in host recognition, attachment, and degradation in the Mycoparasite Tolypocladium ophioglossoides. G3 (Bethesda). 2016;6 :731-741. DOI: 10.1534/g3.116.027045 - 13.
Marfetán JA, Romero AI, Folgarait PJ. Pathogenic interaction between Escovopsis weberi andLeucoagaricus sp.: Mechanisms involved and virulence levels. Fungal Ecology. 2015;17 :52-61. DOI: 10.1016/j.funeco.2015.04.002 - 14.
Wallace DEE, Asensio JGV, Tomás AAP. Correlation between virulence and genetic structure of Escovopsis strains from leaf-cutting ant colonies in Costa Rica. Microbiology. 2014;160 :1727-1736. DOI: 10.1099/mic.0.073593-0 - 15.
de Man TJB, Stajich JE, Kubicek CP, Teiling C, Chenthamara K, Atanasova L, Druzhinina IS, Levenkova N, Birnbaum SSL, Barribeau SM, Bozick BA, Suen G, Currie CR, Gerardo NM. Small genome of the fungus Escovopsis weberi , a specialized disease agent of ant agriculture. Proceedings of the National Academy of Sciences of the United States of America. 2016;113 :3567-3572. DOI: 10.1073/pnas.1518501113 - 16.
Reynolds HT, Currie CR. Pathogenicity of Escovopsis weberi : The parasite of the attine ant-microbe symbiosis directly consumes the ant-cultivated fungus. Mycologia. 2004;96 :955-959. DOI: 10.1080/15572536.2005.11832895 - 17.
Chamoun R, Aliferis KA, Jabaji S. Identification of signatory secondary metabolites during mycoparasitism of Rhizoctonia solani byStachybotrys elegans . Frontiers in Microbiology. 2015;6 :353. DOI: 10.3389/fmicb.2015.00353 - 18.
Bitsadze N, Siebold M, Koopmann B, von TA. Single and combined colonization of Sclerotinia sclerotiorum sclerotia by the fungal mycoparasitesConiothyrium minitans andMicrosphaeropsis ochracea . Plant Pathology. 2015;64 :690-700. DOI: 10.1111/ppa.12302 - 19.
Palmer JM, Keller NP. Secondary metabolism in fungi: Does chromosomal location matter? Current Opinion in Microbiology. 2010; 13 :431-436. DOI: 10.1016/j.mib.2010.04.008 - 20.
Keller NP, Turner G, Bennett JW. Fungal secondary metabolism – From biochemistry to genomics. Nature Reviews. Microbiology. 2005; 3 :937-947. DOI: 10.1038/nrmicro1286 - 21.
Kubicek CP, Herrera-Estrella A, Seidl-Seiboth V, Martinez DA, Druzhinina IS, Thon M, Zeilinger S, Casas-Flores S, Horwitz BA, Mukherjee PK, Mukherjee M, Kredics L, Alcaraz LD, Aerts A, Antal Z, Atanasova L, Cervantes-Badillo MG, Challacombe J, Chertkov O, McCluskey K, Coulpier F, Deshpande N, von Döhren H, Ebbole DJ, Esquivel-Naranjo EU, Fekete E, Flipphi M, Glaser F, Gómez-Rodríguez EY, Gruber S, Han C, Henrissat B, Hermosa R, Hernández-Oñate M, Karaffa L, Kosti I, Le Crom S, Lindquist E, Lucas S, Lübeck M, Lübeck PS, Margeot A, Metz B, Misra M, Nevalainen H, Omann M, Packer N, Perrone G, Uresti-Rivera EE, Salamov A, Schmoll M, Seiboth B, Shapiro H, Sukno S, Tamayo-Ramos JA, Tisch D, Wiest A, Wilkinson HH, Zhang M, Coutinho PM, Kenerley CM, Monte E, Baker SE, Grigoriev IV. Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma . Genome Biology. 2011;12 :R40. DOI: 10.1186/gb-2011-12-4-r40 - 22.
Velazquez-Robledo R, Contreras-Cornejo HA, Macias-Rodriguez L, Hernandez-Morales A, Aguirre J, Casas-Flores S, Lopez-Bucio J, Herrera-Estrella A. Role of the 4-phosphopantetheinyl transferase of Trichoderma virens in secondary metabolism and induction of plant defense responses. Molecular Plant-Microbe Interactions. 2011;24 :1459-1471. DOI: 10.1094/MPMI-02-11-0045 - 23.
Degenkolb T, Aghcheh RK, Dieckmann R, Neuhof T, Baker SE, Druzhinina IS, Kubicek CP, Brueckner H, Doehren H von. The production of multiple small Peptaibol families by single 14-module peptide synthetases in Trichoderma /Hypocrea. Chemistry & Biodiversity. 2012;9 :499-535. DOI: 10.1002/cbdv.201100212 - 24.
Mukherjee PK, Wiest A, Ruiz N, Keightley A, Moran-Diez ME, McCluskey K, Pouchus YF, Kenerley CM. Two classes of new peptaibols are synthesized by a single non-ribosomal peptide synthetase of Trichoderma virens . The Journal of Biological Chemistry. 2011;286 :4544-4554. DOI: 10.1074/jbc.M110.159723 - 25.
Neumann NKN, Stoppacher N, Zeilinger S, Degenkolb T, Brückner H, Schuhmacher R. The peptaibiotics database - a comprehensive online resource. Chemistry & Biodiversity. 2015; 12 :743-751. DOI: 10.1002/cbdv.201400393 - 26.
Ooka T, Shimojima Y, Akimoto T, Takeda I, Senoh S, Abe J. A new antibacterial peptide “Suzukacillin”. Agricultural and Biological Chemistry. 1966; 30 :700-702. DOI: 10.1080/00021369.1966.10858667 - 27.
Bortolus M, de ZM, Formaggio F, Maniero AL. Alamethicin in bicelles: Orientation, aggregation, and bilayer modification as a function of peptide concentration. Biochimica et Biophysica Acta. 2013; 1828 :2620-2627. DOI: 10.1016/j.bbamem.2013.07.007 - 28.
Degenkolb T, Fog Nielsen K, Dieckmann R, Branco-Rocha F, Chaverri P, Samuels GJ, Thrane U, von DH, Vilcinskas A, Brückner H. Peptaibol, secondary-metabolite, and hydrophobin pattern of commercial biocontrol agents formulated with species of the Trichoderma harzianum complex. Chemistry & Biodiversity. 2015;12 :662-684. DOI: 10.1002/cbdv.201400300 - 29.
Engelberth J. Ion Channel-forming Alamethicin is a potent elicitor of volatile biosynthesis and tendril coiling. Cross talk between Jasmonate and Salicylate signaling in lima bean. Plant Physiology. 2001; 125 :369-377. DOI: 10.1104/pp.125.1.369 - 30.
Viterbo A, Wiest A, Brotman Y, Chet I, Kenerley C. The 18mer peptaibols from Trichoderma virens elicit plant defence responses. Molecular Plant Pathology. 2007;8 :737-746. DOI: 10.1111/j.1364-3703.2007.00430.x - 31.
Schirmböck M, Lorito M, Wang YL, Hayes CK, Arisan-Atac I, Scala F, Harman GE, Kubicek CP. Parallel formation and synergism of hydrolytic enzymes and peptaibol antibiotics, molecular mechanisms involved in the antagonistic action of Trichoderma harzianum against phytopathogenic fungi. Applied and Environmental Microbiology. 1994;60 :4364-4370 - 32.
Lorito M, Farkas V, Rebuffat S, Bodo B, Kubicek CP. Cell wall synthesis is a major target of mycoparasitic antagonism by Trichoderma harzianum . Journal of Bacteriology. 1996;178 :6382-6385. DOI: 10.1128/jb.178.21.6382-6385.1996 - 33.
Shi M, Chen L, Wang X-W, Zhang T, Zhao P-B, Song X-Y, Sun C-Y, Chen X-L, Zhou B-C, Zhang Y-Z. Antimicrobial peptaibols from Trichoderma pseudokoningii induce programmed cell death in plant fungal pathogens. Microbiology. 2012;158 :166-175. DOI: 10.1099/mic.0.052670-0 - 34.
Rodríguez MA, Cabrera G, Gozzo FC, Eberlin MN, Godeas A. Clonostachys rosea BAFC3874 as a Sclerotinia sclerotiorum antagonist: Mechanisms involved and potential as a biocontrol agent. Journal of Applied Microbiology. 2011;110 :1177-1186. DOI: 10.1111/j.1365-2672.2011.04970.x - 35.
Otto A, Laub A, Haid M, Porzel A, Schmidt J, Wessjohann L, Arnold N, Tulasporins A-D. 19-Residue peptaibols from the mycoparasitic fungus Sepedonium tulasneanum . Natural Product Communications. 2016;11 :1821-1824 - 36.
Scharf DH, Brakhage AA, Mukherjee PK. Gliotoxin-bane or boon? Environmental Microbiology. 2016; 18 :1096-1109. DOI: 10.1111/1462-2920.13080 - 37.
Zeilinger S, Gruber S, Bansal R, Mukherjee PK. Secondary metabolism in Trichoderma – Chemistry meets genomics. Fungal Biology Reviews. 2016;30 :74-90. DOI: 10.1016/j.fbr.2016.05.001 - 38.
Howell CR, Stipanovic RD, Lumsden RD. Antibiotic production by strains of Gliocladium virens and its relation to the biocontrol of cotton seedling diseases. Biocontrol Science and Technology. 1993;3 :435-441. DOI: 10.1080/09583159309355298 - 39.
Dong J-Y, He H-P, Shen Y-M, Zhang K-Q. Nematicidal epipolysulfanyldioxopiperazines from Gliocladium roseum . Journal of Natural Products. 2005;68 :1510-1513. DOI: 10.1021/np0502241 - 40.
Zheng C-J, Kim Y-H, Kim W-G. Glioperazine B, as a new antimicrobial agent against Staphylococcus aureus, and glioperazine C: Two new dioxopiperazines from Bionectra byssicola . Bioscience, Biotechnology, and Biochemistry. 2007;71 :1979-1983. DOI: 10.1271/bbb.70167 - 41.
Vargas WA, Mukherjee PK, Laughlin D, Wiest A, Moran-Diez ME, Kenerley CM. Role of gliotoxin in the symbiotic and pathogenic interactions of Trichoderma virens . Microbiology. 2014;160 :2319-2330. DOI: 10.1099/mic.0.079210-0 - 42.
Lorito M, Peterbauer C, Hayes CK, Harman GE. Synergistic interaction between fungal cell wall degrading enzymes and different antifungal compounds enhances inhibition of spore germination. Microbiology. 1994; 140 (Pt. 3):623-629. DOI: 10.1099/00221287-140-3-623 - 43.
Lehner SM, Atanasova L, Neumann NKN, Krska R, Lemmens M, Druzhinina IS, Schuhmacher R. Isotope-assisted screening for iron-containing metabolites reveals a high degree of diversity among known and unknown siderophores produced by Trichoderma spp. Applied and Environmental Microbiology. 2013;79 :18-31. DOI: 10.1128/AEM.02339-12 - 44.
Haas H. Molecular genetics of fungal siderophore biosynthesis and uptake: The role of siderophores in iron uptake and storage. Applied Microbiology and Biotechnology. 2003; 62 :316-330. DOI: 10.1007/s00253-003-1335-2 - 45.
Wallner A, Blatzer M, Schrettl M, Sarg B, Lindner H, Haas H. Ferricrocin, a siderophore involved in intra- and transcellular iron distribution in Aspergillus fumigatus. Applied and Environmental Microbiology. 2009; 75 :4194-4196. DOI: 10.1128/AEM.00479-09 - 46.
Eisendle M, Schrettl M, Kragl C, Müller D, Illmer P, Haas H. The intracellular siderophore ferricrocin is involved in iron storage, oxidative-stress resistance, germination, and sexual development in Aspergillus nidulans . Eukaryotic Cell. 2006;5 :1596-1603. DOI: 10.1128/EC.00057-06 - 47.
Oide S, Krasnoff SB, Gibson DM, Turgeon BG. Intracellular siderophores are essential for ascomycete sexual development in heterothallic Cochliobolus heterostrophus and homothallicGibberella zeae . Eukaryotic Cell. 2007;6 :1339-1353. DOI: 10.1128/EC.00111-07 - 48.
Segarra G, Casanova E, Avilés M, Trillas I. Trichoderma asperellum strain T34 controlsFusarium wilt disease in tomato plants in soilless culture through competition for iron. Microbial Ecology. 2010;59 :141-149. DOI: 10.1007/s00248-009-9545-5 - 49.
Shaw S, Le Cocq K, Paszkiewicz K, Moore K, Winsbury R, de Torres Zabala M, Studholme DJ, Salmon D, Thornton CR, Grant MR. Transcriptional reprogramming underpins enhanced plant growth promotion by the biocontrol fungus Trichoderma hamatum GD12 during antagonistic interactions withSclerotinia sclerotiorum in soil. Molecular Plant Pathology. 2016;17 :1425-1441. DOI: 10.1111/mpp.12429 - 50.
Sun X, Zhao Y, Jia J, Xie J, Cheng J, Liu H, Jiang D, Fu Y. Uninterrupted expression of CmSIT1 in a sclerotial parasite Coniothyrium minitans leads to reduced growth and enhanced antifungal ability. Frontiers in Microbiology. 2017; 8 :2208. DOI: 10.3389/fmicb.2017.02208 - 51.
Karlsson M, Durling MB, Choi J, Kosawang C, Lackner G, Tzelepis GD, Nygren K, Dubey MK, Kamou N, Levasseur A, Zapparata A, Wang J, Amby DB, Jensen B, Sarrocco S, Panteris E, Lagopodi AL, Pöggeler S, Vannacci G, Collinge DB, Hoffmeister D, Henrissat B, Lee Y-H, Jensen DF. Insights on the evolution of mycoparasitism from the genome of Clonostachys rosea . Genome Biology and Evolution. 2015;7 :465-480. DOI: 10.1093/gbe/evu292 - 52.
Zhai M-M, Qi F-M, Li J, Jiang C-X, Hou Y, Shi Y-P, Di D-L, Zhang J-W, Weu Q-X. Isolation of secondary metabolites from the soil-derived fungus Clonostachys rosea YRS-06, a biological control agent, and evaluation of antibacterial activity. Journal of Agricultural and Food Chemistry. 2016;64 :2298-2306. DOI: 10.1021/acs.jafc.6b00556 - 53.
Putri SP, Kinoshita H, Ihara F, Igarashi Y, Nihira T. Ophiosetin, a new tetramic acid derivative from the mycopathogenic fungus Elaphocordyceps ophioglossoides . The Journal of Antibiotics. 2010;63 :195-198. DOI: 10.1038/ja.2010.8 - 54.
Kneifel H, König WA, Loeffler W, Müller R. Ophiocordin, an antifungal antibiotic of Cordyceps ophioglossoides . Archives of Microbiology. 1977;113 :121-130. DOI: 10.1007/BF00428591 - 55.
Atanasova L, Knox BP, Kubicek CP, Druzhinina IS, Baker SE. The polyketide synthase gene pks4 of Trichoderma reesei provides pigmentation and stress resistance. Eukaryotic Cell. 2013;12 :1499-1508. DOI: 10.1128/EC.00103-13 - 56.
Schmidt-Dannert C. Biosynthesis of terpenoid natural products in fungi. Advances in Biochemical Engineering/Biotechnology. 2015; 148 :19-61. DOI: 10.1007/10_2014_283 - 57.
Bansal R, Mukherjee PK. The terpenoid biosynthesis toolkit of Trichoderma . Natural Product Communications. 2016;11 :431-434 - 58.
Cardoza RE, Malmierca MG, Hermosa MR, Alexander NJ, McCormick SP, Proctor RH, Tijerino AM, Rumbero A, Monte E, Gutiérrez S. Identification of loci and functional characterization of trichothecene biosynthesis genes in filamentous fungi of the genus Trichoderma . Applied and Environmental Microbiology. 2011;77 :4867-4877. DOI: 10.1128/AEM.00595-11 - 59.
Stoppacher N, Kluger B, Zeilinger S, Krska R, Schuhmacher R. Identification and profiling of volatile metabolites of the biocontrol fungus Trichoderma atroviride by HS-SPME-GC-MS. Journal of Microbiological Methods. 2010;81 :187-193. DOI: 10.1016/j.mimet.2010.03.011 - 60.
Mukherjee M, Horwitz BA, Sherkhane PD, Hadar R, Mukherjee PK. A secondary metabolite biosynthesis cluster in Trichoderma virens : Evidence from analysis of genes underexpressed in a mutant defective in morphogenesis and antibiotic production. Current Genetics. 2006;50 :193-202. DOI: 10.1007/s00294-006-0075-0 - 61.
Crutcher FK, Parich A, Schuhmacher R, Mukherjee PK, Zeilinger S, Kenerley CM. A putative terpene cyclase, vir4, is responsible for the biosynthesis of volatile terpene compounds in the biocontrol fungus Trichoderma virens . Fungal Genetics and Biology. 2013;56 :67-77. DOI: 10.1016/j.fgb.2013.05.003 - 62.
Cardoza RE, Hermosa MR, Vizcaíno JA, González F, Llobell A, Monte E, Gutiérrez S. Partial silencing of a hydroxy-methylglutaryl-CoA reductase-encoding gene in Trichoderma harzianum CECT 2413 results in a lower level of resistance to lovastatin and lower antifungal activity. Fungal Genetics and Biology. 2007;44 :269-283. DOI: 10.1016/j.fgb.2006.11.013 - 63.
Malmierca MG, Cardoza RE, Alexander NJ, McCormick SP, Hermosa R, Monte E, Gutiérrez S. Involvement of Trichoderma trichothecenes in the biocontrol activity and induction of plant defense-related genes. Applied and Environmental Microbiology. 2012;78 :4856-4868. DOI: 10.1128/AEM.00385-12 - 64.
Malmierca MG, Cardoza RE, Alexander NJ, McCormick SP, Collado IG, Hermosa R, Monte E, Gutiérrez S. Relevance of trichothecenes in fungal physiology: Disruption of tri5 in Trichoderma arundinaceum . Fungal Genetics and Biology. 2013;53 :22-33. DOI: 10.1016/j.fgb.2013.02.001 - 65.
Malmierca MG, McCormick SP, Cardoza RE, Monte E, Alexander NJ, Gutiérrez S. Trichodiene production in a Trichoderma harzianum erg1-silenced strain provides evidence of the importance of the sterol biosynthetic pathway in inducing plant Defense-related gene expression. Molecular Plant-Microbe Interactions. 2015;28 :1181-1197. DOI: 10.1094/MPMI-06-15-0127-R - 66.
Cardoza RE, McCormick SP, Malmierca MG, Olivera ER, Alexander NJ, Monte E, Gutiérrez S. Effects of trichothecene production on the plant Defense response and fungal physiology: Overexpression of the Trichoderma arundinaceum tri4 gene in T. Harzianum. Applied and Environmental Microbiology. 2015;81 :6355-6366. DOI: 10.1128/AEM.01626-15 - 67.
Tijerino A, Cardoza RE, Moraga J, Malmierca MG, Vicente F, Aleu J, Collado IG, Gutiérrez S, Monte E, Hermosa R. Overexpression of the trichodiene synthase gene tri5 increases trichodermin production and antimicrobial activity in Trichoderma brevicompactum . Fungal Genetics and Biology. 2011;48 :285-296. DOI: 10.1016/j.fgb.2010.11.012 - 68.
Tijerino A, Hermosa R, Cardoza RE, Moraga J, Malmierca MG, Aleu J, Collado IG, Monte E, Gutierrez S. Overexpression of the Trichoderma brevicompactum tri5 gene: Effect on the expression of the trichodermin biosynthetic genes and on tomato seedlings. Toxins (Basel). 2011;3 :1220-1232. DOI: 10.3390/toxins3091220 - 69.
Atanasova L, Le Crom S, Gruber S, Coulpier F, Seidl-Seiboth V, Kubicek CP, Druzhinina IS. Comparative transcriptomics reveals different strategies of Trichoderma mycoparasitism . BMC Genomics. 2013;14 :121. DOI: 10.1186/1471-2164-14-121 - 70.
Netzker T, Fischer J, Weber J, Mattern DJ, König CC, Valiante V, Schroeckh V, Brakhage AA. Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters. Frontiers in Microbiology. 2015; 6 :299. DOI: 10.3389/fmicb.2015.00299 - 71.
Rubio MB, Hermosa R, Reino JL, Collado IG, Monte E. Thctf1 transcription factor of Trichoderma harzianum is involved in 6-pentyl-2H-pyran-2-one production and antifungal activity. Fungal Genetics and Biology. 2009;46 :17-27. DOI: 10.1016/j.fgb.2008.10.008 - 72.
Rubio MB, Pardal AJ, Cardoza RE, Gutiérrez S, Monte E, Hermosa R. Involvement of the transcriptional coactivator ThMBF1 in the biocontrol activity of Trichoderma harzianum . Frontiers in Microbiology. 2017;8 :2273. DOI: 10.3389/fmicb.2017.02273 - 73.
Alkhayyat F, Yu J-H. Upstream regulation of Mycotoxin biosynthesis. Advances in Applied Microbiology. 2014; 86 :251-278. DOI: 10.1016/B978-0-12-800262-9.00005-6 - 74.
Reithner B, Schuhmacher R, Stoppacher N, Pucher M, Brunner K, Zeilinger S. Signaling via the Trichoderma atroviride mitogen-activated protein kinase Tmk 1 differentially affects mycoparasitism and plant protection. Fungal Genetics and Biology. 2007;44 :1123-1133. DOI: 10.1016/j.fgb.2007.04.001 - 75.
Mukherjee M, Mukherjee PK, Kale SP. cAMP signalling is involved in growth, germination, mycoparasitism and secondary metabolism in Trichoderma virens . Microbiology. 2007;153 :1734-1742. DOI: 10.1099/mic.0.2007/005702-0 - 76.
Reithner B, Brunner K, Schuhmacher R, Peissl I, Seidl V, Krska R, Zeilinger S. The G protein alpha subunit Tga1 of Trichoderma atroviride is involved in chitinase formation and differential production of antifungal metabolites. Fungal Genetics and Biology. 2005;42 :749-760. DOI: 10.1016/j.fgb.2005.04.009 - 77.
Zeilinger S, Reithner B, Scala V, Peissl I, Lorito M, Mach RL. Signal transduction by Tga3, a novel G protein alpha subunit of Trichoderma atroviride . Applied and Environmental Microbiology. 2005;71 :1591-1597. DOI: 10.1128/AEM.71.3.1591-1597.2005 - 78.
Bayram O, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O, Braus-Stromeyer S, Kwon N-J, Keller NP, Yu J-H, Braus GH. VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science. 2008; 320 :1504-1506. DOI: 10.1126/science.1155888 - 79.
Mukherjee PK, Kenerley CM. Regulation of morphogenesis and biocontrol properties in Trichoderma virens by a VELVET protein, Vel1. Applied and Environmental Microbiology. 2010;76 :2345-2352. DOI: 10.1128/AEM.02391-09 - 80.
Karimi Aghcheh R, Druzhinina IS, Kubicek CP. The putative protein methyltransferase LAE1 of Trichoderma atroviride is a key regulator of asexual development and mycoparasitism. PLoS One. 2013;8 :e67144. DOI: 10.1371/journal.pone.0067144 - 81.
Okada BK, Seyedsayamdost MR. Antibiotic dialogues: Induction of silent biosynthetic gene clusters by exogenous small molecules. FEMS Microbiology Reviews. 2017; 41 :19-33. DOI: 10.1093/femsre/fuw035 - 82.
Cutler HG, Cox RH, Crumley FG, Cole PD. 6-Pentyl-α-pyrone from Trichoderma harzianum : Its plant growth inhibitory and antimicrobial properties. Agricultural and Biological Chemistry. 1986;50 :2943-2945. DOI: 10.1080/00021369.1986.10867860 - 83.
Scarselletti R, Faull JL. In vitro activity of 6-pentyl-α-pyrone, a metabolite of Trichoderma harzianum , in the inhibition ofRhizoctonia solani andFusarium oxysporum f. sp.lycopersici . Mycological Research. 1994;98 :1207-1209. DOI: 10.1016/S0953-7562(09)80206-2 - 84.
El-Hasan A, Walker F, Buchenauer H. Trichoderma harzianum and its metabolite 6-pentyl-alpha-pyrone suppress fusaric acid produced byFusarium moniliforme . Journal of Phytopathology. 2008;156 :79-87. DOI: 10.1111/j.1439-0434.2007.01330.x - 85.
Cooney JM, Lauren DR, Di Menna ME. Impact of competitive fungi on trichothecene production by Fusarium graminearum . Journal of Agricultural and Food Chemistry. 2001;49 :522-526. DOI: 10.1021/jf0006372 - 86.
Lutz MP, Feichtinger G, Defago G, Duffy B. Mycotoxigenic Fusarium and deoxynivalenol production repress chitinase gene expression in the biocontrol agentTrichoderma atroviride P1. Applied and Environmental Microbiology. 2003;69 :3077-3084. DOI: 10.1128/AEM.69.6.3077-3084.2003 - 87.
El-Sharkawy S, Abul-Hajj YJ. Microbial cleavage of zearalenone. Xenobiotica. 1988; 18 :365-371. DOI: 10.3109/00498258809041672 - 88.
Tian Y, Tan Y, Liu N, Yan Z, Liao Y, Chen J, de SS, Yang H, Zhang Q, Wu A. Detoxification of deoxynivalenol via glycosylation represents novel insights on antagonistic activities of Trichoderma when confronted withFusarium graminearum . Toxins (Basel). 2016;8 :335. DOI: 10.3390/toxins8110335 - 89.
Malmierca MG, Izquierdo-Bueno I, McCormick SP, Cardoza RE, Alexander NJ, Barua J, Lindo L, Casquero PA, Collado IG, Monte E, Gutiérrez S. Trichothecenes and aspinolides produced by Trichoderma arundinaceum regulate expression of Botrytis cinerea genes involved in virulence and growth. Environmental Microbiology. 2016;18 :3991-4004. DOI: 10.1111/1462-2920.13410 - 90.
Malmierca MG, Izquierdo-Bueno I, McCormick SP, Cardoza RE, Alexander NJ, Moraga J, Gomes EV, Proctor RH, Collado IG, Monte E, Gutiérrez S. Botrydial and botcinins produced by Botrytis cinerea regulate the expression ofTrichoderma arundinaceum genes involved in trichothecene biosynthesis. Molecular Plant Pathology. 2016;17 :1017-1031. DOI: 10.1111/mpp.12343 - 91.
Tian Y, Tan Y, Yan Z, Liao Y, Chen J, de BM, de SS, Wu A. Antagonistic and detoxification potentials of Trichoderma isolates for control of zearalenone (ZEN) producingFusarium graminearum . Frontiers in Microbiology. 2018;8 :2710. DOI: 10.3389/fmicb.2017.02710 - 92.
Chatterjee S, Kuang Y, Splivallo R, Chatterjee P, Karlovsky P. Interactions among filamentous fungi Aspergillus niger, Fusarium verticillioides andClonostachys rosea : Fungal biomass, diversity of secreted metabolites and fumonisin production. BMC Microbiology. 2016;16 :83. DOI: 10.1186/s12866-016-0698-3 - 93.
Vinale F, Nicoletti R, Borrelli F, Mangoni A, Parisi OA, Marra R, Lombardi N, Lacatena F, Grauso L, Finizio S, Lorito M, Woo SL. Co-culture of plant beneficial microbes as source of bioactive metabolites. Scientific Reports. 2017; 7 :14330. DOI: 10.1038/s41598-017-14569-5 - 94.
Watrous JD, Dorrestein PC. Imaging mass spectrometry in microbiology. Nature Reviews. Microbiology. 2011; 9 :683-694. DOI: 10.1038/nrmicro2634 - 95.
Holzlechner M, Reitschmidt S, Gruber S, Zeilinger S, Marchetti-Deschmann M. Visualizing fungal metabolites during mycoparasitic interaction by MALDI mass spectrometry imaging. Proteomics. 2016; 16 :1742-1746. DOI: 10.1002/pmic.201500510 - 96.
Tata A, Perez C, Campos ML, Bayfield MA, Eberlin MN, Ifa DR. Imprint desorption electrospray ionization mass spectrometry imaging for monitoring secondary metabolites production during antagonistic interaction of fungi. Analytical Chemistry. 2015; 87 :12298-12305. DOI: 10.1021/acs.analchem.5b03614