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Review

Secondary Metabolites Produced by Neofusicoccum Species Associated with Plants: A Review

by
Maria Michela Salvatore
1,
Artur Alves
2 and
Anna Andolfi
1,3,*
1
Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy
2
CESAM-Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
3
BAT Center-Interuniversity Center for Studies on Bioinspired Agro-Environmental Technology, University of Naples Federico II, 80055 Portici (NA), Italy
*
Author to whom correspondence should be addressed.
Agriculture 2021, 11(2), 149; https://doi.org/10.3390/agriculture11020149
Submission received: 14 January 2021 / Revised: 4 February 2021 / Accepted: 8 February 2021 / Published: 11 February 2021
(This article belongs to the Special Issue Secondary Metabolites in Plant-Microbe Interactions)
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Abstract

:
The genus Neofusicoccum is comprised of approximately 50 species with a worldwide distribution and is typically associated with plants. Neofusicoccum is well-known for the diseases it causes on economically and ecologically relevant host plants. In particular, members of this genus are responsible for grapevine diseases, such as leaf spots, fruit rots, shoot dieback, bud necrosis, vascular discoloration of the wood, and perennial cankers. Many secondary metabolites, including (−)-botryoisocoumarin A, botryosphaerones, cyclobotryoxide and isosclerone, were identified from species of Neofusicoccum and their structural variability and bioactivities might be associated with the role of these compounds in the fungal pathogenicity and virulence. In this review, we summarize the secondary metabolites from Neofusicoccum species focusing on the role of these compounds in the interaction between the fungus and host plant.

1. Introduction

The genus Neofusicoccum (Dothideomycetes, Botryosphaeriales, Botryosphaeriaceae) was introduced in 2006 to reassign species that were previously included in the genus Fusicoccum and its sexual morph Botryosphaeria [1]. Initially, the genus included 13 species but it has grown considerably, due mainly to the description of a large number of cryptic species, and currently contains about 50 distinct species listed in MycoBank [2] and Index Fungorum [3].
Species in the genus Neofusicoccum are typically associated with plants, being common in a wide range of woody hosts, from forest trees to crops and ornamentals [4,5]. The majority of these species have a worldwide distribution, a plurivorous nature, and exhibit an endophytic or latent pathogen lifestyle. Some Neofusicoccum species are plant pathogens of increasing relevance, causing diseases, most commonly dieback and canker, on economically and ecologically relevant host plants, such as grapevine, olive, eucalypts, among many others [4,5]. Grapevine is a particularly relevant crop worldwide, and several species of Neofusicoccum have been reported to be pathogens of this host. In fact, N. parvum is regarded as one of the most aggressive causal agents of Botryosphaeria dieback of grapevine [6].
In the last decade, literature concerning metabolites produced by Neofusicoccum species has been significantly enriched by many reports dealing with the biosynthetic potential of this fungal genus.
This review is intended as a reference guide to secondary metabolites produced by Neofusicoccum species, emphasizing their role in the fungal association with plants. The main part of this paper comprises over 90 compounds identified as products of Neofusicoccum species and collected in 10 classes on the basis of their chemical structures. Furthermore, some aspects relating to the biosynthesis of these metabolites and related compounds, as well as their bioactivities, are also discussed in dedicated subparagraphs. A final section includes information on the relevance of phytotoxic secondary metabolites produced by Neofusicoccum species associated to grapevine trunk diseases.

2. Secondary Metabolites

Fungi from the genus Neofusicoccum are a promising source of secondary metabolites which can be classified according to their chemical structures. As can be seen from Table 1, compounds produced by Neofusicoccum species belong to different classes of natural products, including 5,6-dihydro-2-pyrones, melleins, myrtucommulones and naphthalenones, which have peculiar biological and chemical features.
Members of the genus Neofusicoccum are often symbiotically associated with different plant species. Symbiotic association between a fungus and a plant is a widespread phenomenon in nature and several symbiotic lifestyles have been defined considering the benefits to or impacts on host and symbiont [7]. Recent studies have indicated that botryosphaeriaceous fungi may express different symbiotic lifestyles in response to host internal signals or environmental factors which also influence the secondary metabolites production [8,9,10,11,12]. In fact, secondary metabolites may have a crucial role in the fungal lifestyles because these compounds have a broad number of biological functions, including mediating communication, nutrient acquisition and acting as virulence factors [13,14].
Neofusicoccum species found as endophytes or pathogens of plants, produce structurally different metabolites. The variety of secondary metabolites produced by diverse species of Neofusicoccum is reported in Table 2, and many compounds showed interesting biological activities (e.g., antibacterial, cytotoxic, phytotoxic).
Diverse species, such as Neofusicoccum australe, Neofusicoccum luteum, Neofusicoccum parvum, and Neofusiccocum vitifusiforme, have been isolated from grapevine (Vitis vinifera) and shown to be pathogenic to this host [15,16,17,18,19,20,21,22,23]. In fact, a long list of secondary metabolites has been identified from these strains and the structural variability might be associated with the role of these compounds in the grapevine diseases. In particular, the capability of N. parvum to colonize woody tissue, combined with the secretion of phytotoxic compounds, is thought to underlie its pathogenicity and virulence [24]. For this reason, a section of this review is dedicated to the phytotoxic activities of secondary metabolites produced by pathogenic strains from grapevine (see Section 3).

2.1. Cyclohexenones

Several compounds belonging to the group of cyclohexenones (Figure 1) were produced by a strain of N. parvum from grapevine. Among them, the most representative is (−)-terremutin (2), a cyclohexanone oxide, identified together with its analogue (+)-epi-sphaeropsidone (6) and the new compound 4-chloro-terremutin hydrate (4) [21]. Cyclobotryoxide (1) is a new metabolite structurally related to 2 produced by a strain of N. australe associated with grapevine dieback [17].
The biosynthesis of (‒)-terramutin is particularly relevant because this compound is a precursor of terreic acid, a potential anticancer drug capable of inhibiting Bruton’s tyrosine kinase [35]. This polyketide is biosynthesized from the condensation of three units of malonyl CoA and a unit of acetyl CoA. 6-Methylsalicylic acid is a cyclic intermediate produced, whose subsequent decarboxylation produces 6-methylcatechol and then terremutin. Interestingly, two precursor phenolic compounds were isolated from cultures of strain producers of 1 and 2 (Table 2).

2.2. 5,6-Dihydro-2-Pyrones

The 6-substituted derivatives of 5,6-dihydropyran-2-ones (or 5,6-dihydro-α-pyrones) are polyketides produced by microorganisms and plants [36,37]. These compounds are characterized by the presence of an α, β unsaturated-δ-lactone, with an alkyl, alkenyl or aryl substituent at C-6 and occasionally a varied substitution pattern around the ring. Many of these products are biologically active, exhibiting phytotoxicity, cytotoxicity against tumor cells and antifungal or antimicrobial activity [36,37].
Asperlin (7) and its diastereomer dia-asperlin (8) (Figure 2) have been isolated from a strain of N. parvum associated with grapevine plants cv. Chardonnay from nursery, showing decline symptoms. (+)-Asperlin was previously reported from cultures of Aspergillus nidulans, while (+)-(6R, 7S)-dia-asperlin was originally reported from Aspergillus caespitosus [21].
Luteopyroxin (9) was obtained from grapevines showing symptoms of Botryosphaeria dieback (see Section 3) in Australian vineyards. This compound was characterized as a (3S,3aR,7aS)-4-methoxy-3-methyl-2,3,3a,7atetrahydro- 6H-furo [2,3b]pyran-6-one. In particular, its relative and absolute configurations have been determined by nuclear Overhauser effect spectroscopy and experimental and calculated electronic circular dichroism data [30]. This metabolite is structurally related to astepyrone isolated from Aspergillus terreus [38].

2.3. Fatty Acids

Fatty acids are essential storage molecules and the starting material for the synthesis of many secondary metabolites [39]. Some long chain fatty acids and their esters (Figure 3) have been detected in culture extracts of strains of N. vitifusiforme and N. parvum [23,34]. Particularly relevant is the finding of linoleic acid (12) as a product of species of Neofusicoccum isolated from grapevine [23]. In fact, this octadecanoid acid may take part in the biosynthesis of jasmonic acid participating in the signaling pathway during pathogen attack and plant colonization [40].

2.4. Melleins

Melleins, also known as 3,4-dihydroisocoumarins, are lactonic natural compounds commonly produced by fungi, bacteria and plants representing a subgroup of the isocoumarins. A large majority of isocoumarins belong to this subgroup characterized by having one carbon substituent at C-3. (-(−)-(R)-Mellein is the founding product of this subgroup first isolated from the fungus Aspergillus melleus (1933) [41]. Several melleins with hydroxyl, methoxyl, alkyl or acetate groups in diverse positions have been subsequently isolated from natural sources [42].
Some compounds belonging to melleins have been reported as phytotoxins produced by pathogens from the family Botryosphaeriaceae [9,11]. Melleins have also been frequently found in cultures of Neofusicoccum species, such as N. australe, N. parvum, N. batangarum, N. luteum (Figure 4) [15,16,32,33]. In particular, (−)-(R)-mellein (24), (3R,4R)-hydroxymellein (26), (3R,4S)-hydroxymellein (27), botryoisocoumarin A (30), and (+)-neoisocoumarin (31) have been isolated from N. batangarum associated with scabby canker of Cactus pear (Opuntia ficus-indica). These compounds showed phytotoxicity on the host and non-host (tomato) plants when tested using the leaf puncture assay and the cladode puncture method. Compounds 30 and 31 are the most active at concentrations in a range from 10−3 to 10−4 M, inducing a necrosis area around the inoculation points [15]. (−)-(R)-Mellein, (3R,4S)- and (3R,4R)- hydroxymelleins were isolated from the first time from a phytopathogenic strain of N. luteum, representing the first detection of phytotoxins from this species [16].
Interestingly, (3R)-5-hydroxymellein (28), isolated from N. parvum, has an effect in the suppression of the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease in negative charges, the reduction in hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, 28 significantly reduced foam cell formation induced by oxidized LDL (oxLDL). These findings show that it could be a potential preventive agent of atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation [33].

2.5. Myrtucommulones

Myrtucommulone A (32) is the founding product of the group of structurally related compounds named myrtucommulones whose structures are characterized by a phloroglucinol nucleus coupled with syncarpic acid residues (Figure 5) [28]. Myrtucommulones and related acylphloroglucinols are frequently reported as products of plant species belonging to the family Myrtaceae (e.g., Eucalyptus globulus [43], Kunzea ericoides [44], Myrtus communis [45,46,47], Melaleuca citrina [48], Rhodomyrtus tomentosa [49,50,51]) spread in the Australasian region and these compounds are well-known for their antimicrobial, antioxidant and anti-inflammatory activities [28]. Some endophytic fungi from the genus Neofusicoccum are able to produce myrtucommulones. This finding represents a new frontier in the study of myrtucommulones because the availability of strains to be cultured in vitro may provide access to increased amounts of these products for further investigations. To date, myrtucommulones A, B and D (32–34) were identified in cultures of endophytic strains of N. australe of myrtle (Myrtus communis) [27,28]. Antiproliferative activity effects on the human prostatic cancer cell lines DU145 and PC3 were observed for a mixture of 32 and 34 [27].

2.6. Naphthalenones

Naphthalenones (Figure 6) are a group of compounds strictly related to napthoquinones. In fact, depending upon prevalent redox conditions, para-quinones can be fully reduced (hydroquinone; QH2), fully oxidized (p-quinone; Q), or in an intermediate (p-semiquinone radical; QH_) oxidation state [52]. It was hypothesized that several naphthoquinones (e.g., flaviolin, juglone, 3-hydroxyjuglone) could be linked to the biosynthesis of naphthalenones (e.g., isosclerone, 4-hydroxyscytalone) through the reduction in the carbonylic group at C-4. Moreover, several naphthalenones epimers at C-4 were isolated as natural products, such as (−)-regiolone and (+)-isosclerone, respectively, isolated from walnut tree (Juglans regia) and the fungus Sclerotinia sclerotium [53], (−)- and (+)-leptothalenones A from the marine-derived fungus Leptosphaerulina chartarum [54]. Finally, as can be seen from Table 2, compounds from both naphthalenones and naphthoquinones groups were isolated as products of the secondary metabolism of diverse species of Neofusicoccum. In particular, 6-ethyl-2,7-dimethoxyyjuglone (47) and its 4-dihydroderivate, (3R,4R)-3-methoxyl-botryosphaerone D (42), were isolated from N. australe [26].
Among the fungal naphthalenones producers, a strain of Botryosphaeria australis (=N. australe) originally obtained from the epidermis of the mangrove plant Sonneratia apetala, is particularly relevant for the capacity to synthesize some new tri-substituted naphthalenones named botryosphaerones A–D (35–38) [29] which showed cytotoxicity against HeLa, HepG-2, and A-549 cells at a concentration of 10 μg mL−1, and antimicrobial activities against pathogenic bacteria or yeasts at a concentration of 50 μg mL−1. Subsequently, naphthalenones were isolated from cultures of Neofusicoccum species involved in grapevine diseases. This is the case of a strain of N. australe involved in branch dieback of Juniperus phoenicea in Sardinia (Italy) which produced botryosphaerone D (37) and (3S,4S)-3,4,8-trihydroxy-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (44) [17], a phytopathogenic strain of N. parvum isolated from declining vines in Sicily (Italy) which produced botryosphaerones A (35) and D (38), isosclerone (39), and 3,4,5-trihydroxy-1-tetralone (42) [19] and a strain of N. parvum obtained from a cankered branch of grapevine growing in Catalogna (Spain) which produced 39 representing the first detection of this compound as a product of botryosphaeriaceous fungi [20].

2.7. Naphthoquinones

As can be seen from Table 2, different species of Neofusicoccum show the production of 1,4-naphtoquinones. Natural naphthoquinone derivatives have been widely identified as functional metabolites from various plants, microbes, and marine organisms [55]. For their notable activities, this class of compounds is the prime target of a vigorous research activity focused on the development of new therapeutic agents [56]. Furthermore, naphtoquinones are also relevant because of their bioactivities. In fact, naphthoquinones have a very interesting spectrum of biological activities, including antibiotic, antiviral, anti-inflammatory, antipyretic, antiproliferative and cytotoxic effects, which are related to several mechanisms of action, such as redox cycles, arylation of the thiol groups of proteins, intercalation, induction of breaks in the DNA chain, generation of free radicals and other reactive oxygen species (ROS) and bioreductive alkylation via the formation of quinone methide [57].
Seven naphthoquinones have been isolated from Neofusicoccum species (Figure 7). The most significant structural differences are the presence of hydroxyl, methoxyl, alkyl or acetate groups in different positions on the 1,4-naphthalenoid ring, but these compounds share the hydroxy group at C-5 and the methoxy groups at C-2 and C-7. These groups are all present in the 5-hydroxy-2,7-dimethoxynaphthalene-1,4-dione (50) [25], which was identified as a product of an endophytic strain of B. australis (=N. australe) isolated from the mangrove plant Avicennia marina, together with botryosphaenin (45), a new naphtoquinone. This latter compound and its 6-ethyl analogue (6-ethyl-5-hydroxy-2,7-dimethoxynaphthalene-1,4-dione 47) showed antibiotic and antiproliferative activities with a minimum inhibitory concentration (MIC) ranging from 2 to 32 μg mL−1 when tested on Gram-positive bacteria and an IC50 value from 0.5 to 2 μg mL−1 when tested on different cell lines [25].
New ethylnaphthoquinones have been isolated from a mangrove endophytic strain of N. australe. In particular, an unsymmetrical naphthoquinone dimer, 6-(1-methoxylethyl)-2,7-dimethoxyjuglone (49), and a naphthalenone named (3R,4R)-3-methoxyl-botryosphaerone (42), together with some known analogues. Indoleamine 2,3-dioxygenase (IDO) inhibitory activity tests showed that, among the isolated compounds, the most active was 6-(1-methoxylethyl)-2,7-dimethoxyjuglone (49) with an IC50 value of 0.11 μM [26].

2.8. Phenols and Alcohols

Phenol derivative compounds (Figure 8) are among the most common metabolites of microorganisms and plants. In particular, phenyl ethanol (60) and tyrosol (61) are produced by fungi via the Shikimate biosynthetic pathway, while 2-hydroxypropylsalicylic acid (53) and 6-methylsalicylic acid (56) are produced through the Polyketide biosynthetic pathway. Tyrosol is one of the most frequently detected metabolites in cultures of botryosphaeraceous fungi [58]. In fact, it was identified in culture extracts of several phytopathogenic strains of N. australe [16,17,30], N. parvum [30,32] and N. luteum [18,30] (Table 2).
As reported above, 6-methylsalicylic acid, together with (−)-terremutin (2), takes part in the biosynthesis of the terric acid [35] and, interestingly, these compounds were both identified as products of a strain of N. parvum isolated from grapevine [21].

2.9. Sesquiterpenes

Fungal sesquiterpenes are essentially hydrocarbons possessing a multitude of different carbons skeletons. Starting from farnesol-pyrophosphate, the sesquiterpene skeleton is cyclized by different sesquiterpene cyclases producing the cations germacryl, humulyn, bisabolyn [59,60]. As often reported for secondary metabolites [8,9,10,11], sesquiterpenes biosynthesis is highly dependent on growth conditions (e.g., temperature, pH, humidity, growth substrate), but little is known about the fungal biosynthesis. On the contrary, there is ample literature on the biosynthesis of sesquiterpenes by plants [61,62,63].
The volatile fraction of sesquiterpenes consists mainly of lipophilic compounds and this suggests that their principal targets are cell membranes causing toxic effects due to the loss of osmotic control [64]. Another possibility is that volatile sesquiterpenes facilitate the passage of other toxins through membranes by acting as solvents and synergizing their effects [65].
The headspace-solid phase micro-extraction (HS-SPME) approach was used by Oliveira et al. [31] to efficiently extract the volatile fraction of metabolites in vitro produced by different Botryosphaeriaceae species. Among them, endophytic strains of Neofusicoccum cordaticola, Neofusicoccum ribis and N. parvum were investigated. The fungal extracts were analyzed via gas chromatography-mass spectrometry (GC-MS) and identified by comparing their mass spectrum with those present in mass spectral libraries. These three Neofusicoccum strains showed the production of different subgroup of sesquiterpenes, including eudesmane, guaiane, cadinane, cedrane, aristolane, valencane, copaene and eremophylane skeletons, and two monocyclic sesquiterpenes (i.e., β-elemene and germacrene D) (Figure 9). The non-oxygenated sesquiterpenes belong mostly to the cadinane group while the oxygenated ones possess the guaiane and cedrane skeleton. Interestingly, in this study, many sesquiterpenes were reported for the first time as fungal metabolites, such as aristolene (62), aristolochene (63), α-cadinol (67), α-cedrene epoxide (68), β-cedren2-one (69), 5-neo-cedranol (71), γ-cadinene (72), δ-cadinene (73), eremophylene (75), guaiol acetate (78), juniper camphor (79), trans-cadina-1(2)4-diene (81). As said above, sesquiterpenes are mainly reported as plant metabolites and their production by endophytes can be explained considering that these fungi are able to produce many plant-derived compounds through the so-called horizontal gene transfer (HGT) [66,67]. In fact, it has been hypothesized that plant-microbe interactions may lead to HGT or genetic recombination, from the host plant to its endophytic counterpart or vice versa, that subsequently, lead to endophytes capable of accumulating certain metabolites specific to the host plants themselves [68].
Sesquiterpenes seem interesting in terms of chemotaxonomy [31]. In fact, N. parvum and N. ribis are very closely related species not easy to distinguish even through the use of molecular techniques. Hence, the different production of the sesquiterpenes α-cedrene epoxide (68) and guaiol acetate (78) by these species can help the species identification.

2.10. Miscellaneous

A number of products of Neofusicoccum species are placed in a miscellaneous category (Figure 10) because they have no structural affinity with previous groups. This is the case of luteoethanones A and B (88–89), two phytotoxic 1-substituted ethanones, identified for the first time from the culture extract of N. luteum [18].
Furthermore, a strain of N. luteum isolated from grapevines showing symptoms of Botryosphaeria dieback produced a new trisubstituted oxepi-2(7H)-one named luteoxepinone (87) and several known compounds [30], including the cyclopentenone (±)-nigrosporione (91) [69].
Another interesting compound is (−)-terpestacin isolated from Neofusicoccum batangarum, pathogenic to cactus pear [15]. (−)-Terpestacin has also been isolated from several fungal cultures, in particular from Rutstroemia capillus-albis, the causal agent of bleach blonde syndrome on the Bromus tectorum [70]. In fact, phytotoxic tests showed that this compound is toxic for both host and non-host (tomato) plants confirming its potential role in fungal pathogenesis [15].

3. Phytotoxicity of Neofusicoccum Metabolites on Grapevine

A large number of species of the family Botryosphaeriaceae have been associated with canker and dieback of grapevines. Grapevine trunk diseases (GTDs) are among the prime causes worldwide of serious damages on vineyards and significant economic losses [71,72]. One of the major concerns in GTDs control is the slow progression of the host xylem colonization by pathogenic fungi or the absence of symptoms for long periods [71,73,74]. In the broad spectrum of GTDs, species of Botryosphaeriaceae are the disease causative agent of the Botryosphaeria dieback [12,58,75] and several of these species belong to genus Neofusicoccum, causing diverse symptoms in infected grapevines, such as leaf chlorosis, bud and wood necrosis, weak spring growth, and vascular cankers primarily in the shape of wedges [72,76,77]. Many symptoms, particularly the foliar ones, can be attributed to the production of toxic secondary metabolites by the fungus [11,78].
As reported in Table 3, strains of N. australe, N. luteum, N. parvum, N. vitifusiforme associated with Botryosphaeria dieback produce phytotoxic metabolites. In fact, the phytotoxic activity of some of them has been investigated on leaves, leaf discs or detached leaves of grapevines showing concentration dependent necrosis. As reported by Abou-Mansour et al. [21], (R)-(−)-3-hydroxymellein (25) is the most active mellein tested with 62% leaf disc necrosis. Among cyclohexenones, the compounds with an epoxydic ring are the most active (i.e., cyclobotryoxide (1), (−)-terremutin (2), (+)-epi-sphaeropsidone (6)), while (+)-(6R,7S)-dia-asperlin (8) is responsible for 33% of leaf disc necrosis. Among naphthalenones, the principal phytotoxic compound is botryosphaerone D (38) whose activity is photosensitive [19].
Furthermore, luteoethanones A and B (88–89), luteopyroxin (9), neoanthraquinone (90) and (±)-nigrosporione (91) are responsible for large necrotic spots, severe shriveling, and distortion of the leaf when tested at a concentration of 2.5 mM [18,30].
Concerning the potential involvement of phytotoxins in the symptoms expression by grapevines, a simplified model using grapevine cells (calli) from V. vinifera cv. Chardonnay was employed. In this respect (−)-terremutin and mellein are responsible for the expression of some genes involved in the defense mechanisms of grapevine (e.g., cellular detoxification, jasmonic acid pathway, synthesis of secondary metabolites of the phenylpropanoid pathway, flavonoid synthesis), after 1–6 days of exposure on calli [21,22]. Moreover, these findings confirm the presence and the phytotoxic effects of (−)-terramutin and mellein in grapevine wood from plants showing Botryosphaeria dieback symptoms [21,22]. It seems possible that there is a synergistic action between different fungal metabolites, but the different hypotheses still need to be examined.

4. Conclusions

In this review, the available literature on secondary metabolites produced by Neofusicoccum species has been analyzed. A total of 91 chemically defined compounds from over 20 isolates belonging to 7 species of Neofusicoccum have been reported. These compounds were classified based on their structure in nine groups (i.e., cyclohexenones, 5,6-dihydro-2-pyranones, fatty acids, melleins, myrtocommulones, naphthalenones, naphthoquinones, phenols and alcohols, sesquiterpenes). Furthermore, an additional group of miscellaneous compounds was added in order to gather metabolites that have no structural affinity with compounds present in the reported groups.
An aptitude of members of the Neofusicoccum genus to colonize different plant species, essentially as a latent pathogen, arises from an accurate examination of the existing literature. The pathogenicity and virulence of these fungi seem to be related, at least in part, to the capacity to produce secondary metabolites. Several strains from different species caused similar effects on plants, perhaps due to the production of specific metabolites. In fact, many disease symptoms (e.g., bud necrosis, vascular discoloration of the wood, and perennial cankers) might be caused by metabolites which were detected in cultures of phytopathogenic species of Neofusicoccum. For instance, mellein and its derivatives have been detected in most strains isolated from grapevines showing symptoms of grapevine trunk diseases (GTDs). This evidence is supported by the phytotoxic activity of these compounds on host and non-host plants.
Moreover, metabolites produced by Neofusicoccum species exhibit additional biological activities, including antibacterial, cytotoxic, antiproliferative and indoleamine 2,3-dioxygenase (IDO) inhibitory effects. In this respect, the genus Neofusicoccum can be regarded as a source of bioactive products to be used in diverse biotechnological fields.
The knowledge present in this review can be applied where recommendations for Neofusicoccum disease management strategies are required. In fact, enriching the existing literature with data on secondary metabolites produced by Neofusicoccum isolates from different hosts might be useful for several purposes, such as understanding the resistance mechanisms, screening of diseases, and potential applications of secondary metabolites.

Author Contributions

Conceptualization, A.A. (Artur Alves). and A.A. (Anna Andolfi); writing—review and editing, M.M.S., A.A. (Artur Alves) and A.A. (Anna Andolfi). All authors have read and agreed to the published version of the manuscript.

Funding

Artur Alves acknowledges financial support from FCT/MCTES to CESAM (UIDP/50017/2020 + UIDB/50017/2020), through national funds.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Structures of cyclohexenones: cyclobotryoxide, (−)-terremutin, (+)-terremutin hydrate, 4-chloro-terremutin hydrate, (+)-4-hydroxysuccinate-terremutin hydrate, (+)-epi-sphaeropsidone (1–6).
Figure 1. Structures of cyclohexenones: cyclobotryoxide, (−)-terremutin, (+)-terremutin hydrate, 4-chloro-terremutin hydrate, (+)-4-hydroxysuccinate-terremutin hydrate, (+)-epi-sphaeropsidone (1–6).
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Figure 2. Structures of 5,6-dihydro-2-pyrones: asperlin, dia-asperlin, luteopyroxin (7–9).
Figure 2. Structures of 5,6-dihydro-2-pyrones: asperlin, dia-asperlin, luteopyroxin (7–9).
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Figure 3. Structures of fatty acids: elaidic acid, ethyl elaidate, linoleic acid, ethyl linoleate, methyl linoleate, 9,12,15-octadecatrienoate ethyl ester, ethyl oleate, methyl oleate, palmitic acid, methyl palmitate, palmitoleic acid, stearic acid, ethyl stearate, undecan-2-one (10–23).
Figure 3. Structures of fatty acids: elaidic acid, ethyl elaidate, linoleic acid, ethyl linoleate, methyl linoleate, 9,12,15-octadecatrienoate ethyl ester, ethyl oleate, methyl oleate, palmitic acid, methyl palmitate, palmitoleic acid, stearic acid, ethyl stearate, undecan-2-one (10–23).
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Figure 4. Structures of melleins: (R)-(−)-mellein, (R)-(−)-3-hydroxymellein, (3R,4R)-(−)-4-hydroxymellein, (3R,4S)-(−)-4-hydroxymellein, (3R)-5-hydroxymellein, 7-hydroxymellein, (±)-botryoisocoumarin A, (+)-neoisocoumarin (24–31).
Figure 4. Structures of melleins: (R)-(−)-mellein, (R)-(−)-3-hydroxymellein, (3R,4R)-(−)-4-hydroxymellein, (3R,4S)-(−)-4-hydroxymellein, (3R)-5-hydroxymellein, 7-hydroxymellein, (±)-botryoisocoumarin A, (+)-neoisocoumarin (24–31).
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Figure 5. Structures of myrtocommulones: myrtucommulone A, B and D (32–34).
Figure 5. Structures of myrtocommulones: myrtucommulone A, B and D (32–34).
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Figure 6. Structures of naphthalenones: botryosphaerones A–D, isosclerone, O-methylasparvenone, O-methylaspmenone, (3R,4R)-3-methoxyl-botryosphaerone D, 3,4,5-trihydroxy-1-tetralone, (3S,4S)-3,4,8-trihydroxy-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (35–44).
Figure 6. Structures of naphthalenones: botryosphaerones A–D, isosclerone, O-methylasparvenone, O-methylaspmenone, (3R,4R)-3-methoxyl-botryosphaerone D, 3,4,5-trihydroxy-1-tetralone, (3S,4S)-3,4,8-trihydroxy-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (35–44).
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Figure 7. Structures of naphthoquinones: botryosphaenin, neofusnaphthoquinone A, 6-ethyl-2,7-dimethoxyyjuglone, 6-(1-hydroxyethyl)-2,7-dimethoxyjuglone, 6-(1-methoxylethyl)-2,7-dimethoxyjuglone, 6-(1-hydroxyethyl)-2,7-dimethoxyjuglone monoacetate, 5-hydroxy-2,7-dimethoxynaphthalene-1,4-dione (45–51).
Figure 7. Structures of naphthoquinones: botryosphaenin, neofusnaphthoquinone A, 6-ethyl-2,7-dimethoxyyjuglone, 6-(1-hydroxyethyl)-2,7-dimethoxyjuglone, 6-(1-methoxylethyl)-2,7-dimethoxyjuglone, 6-(1-hydroxyethyl)-2,7-dimethoxyjuglone monoacetate, 5-hydroxy-2,7-dimethoxynaphthalene-1,4-dione (45–51).
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Figure 8. Structures of phenols and alcohols: 2-ethyldecan-1-ol, 2-hydroxypropyl salicylic acid, 2-methylbutan-1-ol, 3-methylcatechol, 6-methyl-salicylic acid, isobutanol, isopentyl alcohol, p-cresol, phenylethyl alcohol, tyrosol (52–61).
Figure 8. Structures of phenols and alcohols: 2-ethyldecan-1-ol, 2-hydroxypropyl salicylic acid, 2-methylbutan-1-ol, 3-methylcatechol, 6-methyl-salicylic acid, isobutanol, isopentyl alcohol, p-cresol, phenylethyl alcohol, tyrosol (52–61).
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Figure 9. Structures sesquiterpenes: aristolene, aristolochene, δ-amorphene, botryosterpene, calarene, α-cadinol, α-cedrene epoxide, β-cedren-9-one, α-copaene, 5-neo-cedranol, γ-cadinene, δ-cadinene, β-elemene, ermophylene, germacrene D, globulol, guaiol acetate, juniper camphor, α-selinene, trans-cadina-1(2)-4-diene, valecene, zonarene (62–83).
Figure 9. Structures sesquiterpenes: aristolene, aristolochene, δ-amorphene, botryosterpene, calarene, α-cadinol, α-cedrene epoxide, β-cedren-9-one, α-copaene, 5-neo-cedranol, γ-cadinene, δ-cadinene, β-elemene, ermophylene, germacrene D, globulol, guaiol acetate, juniper camphor, α-selinene, trans-cadina-1(2)-4-diene, valecene, zonarene (62–83).
Agriculture 11 00149 g009
Agriculture 11 00149 g010 550
Figure 10. Structures of compounds from the group “miscellaneous”: azelaic acid, 5-(carboxymethyl)-7-hydroxy-1,4a-dimethyl-6-methylene decahydronaphthalene-1-carboxylic acid, (−)-terpestacin, luteoxepinone, luteoethanones A-B, luteoethanone B, neoanthraquinone, (±)-nigrosporione (84–91).
Figure 10. Structures of compounds from the group “miscellaneous”: azelaic acid, 5-(carboxymethyl)-7-hydroxy-1,4a-dimethyl-6-methylene decahydronaphthalene-1-carboxylic acid, (−)-terpestacin, luteoxepinone, luteoethanones A-B, luteoethanone B, neoanthraquinone, (±)-nigrosporione (84–91).
Agriculture 11 00149 g010
Table
Table 1. List of secondary metabolites produced by Neofusicoccum species.
Table 1. List of secondary metabolites produced by Neofusicoccum species.
CodeCompoundFormulaNominal Mass (U)
Cyclohexenones
1CyclobotryoxideC8H10O4170
2(−)-TerremutinC7H8O4156
3(+)-Terremutin hydrateC7H10O5174
4(−)-4-Chloro-terremutin hydrateC7H9ClO4192
5(+)-4-Hydroxysuccinate-terremutin hydrateC11H14O8274
6(+)-epi-SphaeropsidoneC7H8O4156
5,6-Dihydro-2-pyrones
7AsperlinC10H12O5212
8(6R,7S)-Dia-asperlinC10H12O5212
9LuteopyroxinC9H12O4184
Fatty acids
10Elaidic acidC18H34O2282
11Ethyl elaidateC20H38O2310
12Linoleic acidC18H32O2280
13Ethyl linoleateC20H36O2308
14Methyl linoleateC19H34O2294
159,12,15-Octadecatrienoate ethyl esterC20H34O2306
16Ethyl oleateC20H38O2310
17Methyl oleateC19H36O2296
18Palmitic acidC16H32O2256
19Methyl palmitateC17H34O2270
20Palmitoleic acidC16H30O2254
21Stearic acidC18H36O2284
22Ethyl stearateC20H40O2312
23Undecan-2-oneC11H22O170
Melleins
24(R)-(−)-MelleinC10H10O3178
25(R)-(−)-3-HydroxymelleinC10H10O4194
26(3R,4R)-(−)-4-HydroxymelleinC10H10O4194
27(3R,4S)-(−)-4-HydroxymelleinC10H10O4194
28(3R)-5-HydroxymelleinC10H10O4194
297-HydroxymelleinC10H10O4194
30(±)-Botryoisocoumarin AC11H12O4208
31(+)-NeoisocoumarinC10H10O5210
Myrtucommulones
32Myrtucommulone AC38H52O10668
33Myrtocommulone BC24H30O6414
34Myrtucommulone DC38H50O9650
Naphthalenones
35Botryosphaerone AC13H16O6268
36Botryosphaerone BC13H16O6268
37Botryosphaerone CC14H18O6282
38Botryosphaerone DC13H16O5252
39IsoscleroneC11H12O2176
40O-MethylasparvenoneC13H16O4236
41O-MethylaspmenoneC10H10O3178
42(3R,4R)-3-Methoxyl-botryosphaerone DC14H18O5266
433,4,5-Trihydroxy-1-tetraloneC10H10O4194
44(3S,4S)-3,4,8-Trihydroxy-6-methoxy-3,4-
dihydro-1(2H)-naphthalenone		C11H12O5224
Naphthoquinones
45BotryosphaeninC15H16O6292
46Neofusnaphthoquinone AC27H24O10508
476-Ethyl-
2,7-dimethoxyyjuglone		C14H14O5262
486-(1-Hydroxyethyl)-2,7-
Dimethoxyjuglone		C14H14O6278
496-(1-Methoxylethyl)-
2,7-dimethoxyjuglone		C15H16O6292
506-(1-Hydroxyethyl)-2,7-
dimethoxyjuglone monoacetate		C16H16O7320
515-Hydroxy-2,7-dimethoxynaphthalene-1,4-dioneC12H10O5234
Phenols and alcohols
522-Ethyldecan-1-olC12H26O186
532-Hydroxypropyl salicylic acidC10H12O4196
542-Methylbutan-1-olC5H12O88
553-MethylcatecholC7H8O2124
566-Methyl-salicylic acidC8H8O3152
57IsobutanolC4H10O74
58Isopentyl alcoholC5H12O88
59p-CresolC7H8O108
60Phenylethyl alcoholC8H10O122
61TyrosolC8H10O2138
Sesquiterpenes
62AristoleneC15H24204
63AristolocheneC15H24204
64δ-AmorpheneC15H24204
65BotryosterpeneC16H22O3262
66CalareneC15H24204
67α-CadinolC15H26O222
68α-Cedrene epoxideC15H24O220
69β-Cedren-9-oneC15H24204
70α-CopaeneC15H24204
715-Neo-cedranolC14H24O208
72γ-CadineneC15H24204
73δ-CadineneC15H24204
74β-ElemeneC15H24204
75ErmophyleneC15H24204
76Germacrene DC15H24204
77GlobulolC15H26O222
78Guaiol acetateC17H28O2264
79Juniper camphorC15H26O222
80α-SelineneC15H24204
81Trans-cadina-1(2)-4-dieneC15H24204
82ValeceneC15H24204
83ZonareneC15H24204
Miscellaneous
84Azelaic acidC9H16O4188
855-(Carboxymethyl)-7-hydroxy-1,4a-dimethyl-6-methylene decahydron
aphthalene-1-carboxylic acid		C16H24O5296
86(−)-TerpestacinC25H38O4402
87LuteoxepinoneC9H12O4184
88Luteoethanone AC11H15NO3209
89Luteoethanone BC10H13NO3195
90NeoanthraquinoneC18H16O4296
91(±)-NigrosporioneC8H10O4170
Table
Table 2. Occurrence of secondary metabolites in Neofusicoccum species.
Table 2. Occurrence of secondary metabolites in Neofusicoccum species.
SpeciesStrainHost (Lifestyle)Identified CompoundsBioactivityRef.
N. australe (=Botryosphaeria australis)AMCL7Avicennia marina (endophyte)40 *, 41, 45, 47, 51, 65, 85Antibacterial, cytotoxic[25]
BL24Juniper phoenicea (pathogen)38, 44, 61Phytotoxic[17]
SYSU-SKS024Kandelia candel (endophyte)36, 38, 40, 42, 46–50IDO inhibitory[26]
E54MLMyrtus communis (endophyte)32,34Antiproliferative[27]
A1304BM. communis (endophyte)33Phytotoxic[28]
ZJ12-1ASonneratia apetala (epiphyte)35–38, 40, 41, 47, 50 [29]
BOT48Vitis vinifera (pathogen)1, 55, 61 [17]
VP13V. vinifera (pathogen)24, 61 [16]
DAR79506V. vinifera (pathogen)24, 59, 90, 61Phytotoxic[30]
N. batangarumCBS143023Opuntia ficus-indica (pathogen)24, 26, 27, 30, 31, 86Phytotoxic[15]
N. cordaticola434(endophyte)23, 52, 54, 57, 58, 60, 62–64, 66–70, 73–76, 78, 80, 82, 83 [31]
N. luteumB175V. vinifera (pathogen)24, 26, 27, 61 [16]
DAR81016V. vinifera (pathogen)9, 24, 26, 27, 61, 87–91Phytotoxic[18,30]
N. parvum (=B. parva)-Eugenia jambolana (endophyte)24, 28, 29 [32]
600(endophyte)23, 52, 54, 57, 58, 60, 63, 66–69, 72, 74, 76, 77–80 [31]
JS-0968Vitis rotundifolia (endophyte)28Anti-atherosclerotic[33]
2S-16V. vinifera (pathogen)2–8, 24–27, 53, 56,Phytotoxic[21]
CBS 121486V. vinifera (pathogen)26, 27, 39, 61Phytotoxic[20]
B19V. vinifera (pathogen)12, 13, 21, 35, 38, 39, 43,Phytotoxic[19,23]
Bt67V. vinifera (pathogen)24Phytotoxic[22]
S-116V. vinifera (pathogen)24Phytotoxic[22]
DAR80004V. vinifera (pathogen)24, 26, 27, 61 [30]
UCD646So-11, 13–19, 22 [34]
N. ribis683(endophyte)23, 54, 57, 58, 60, 62, 64, 66–69, 71, 73–83 [31]
N. vitifusiformeB8V. vinifera (pathogen)10, 12, 18, 20, 21, 84 [23]
* In the original paper the authors report the structure of botryosphaerone D instead of O-methylasparvenone.
Table
Table 3. Phytotoxicity of metabolites produced by Neofusicoccum species on grapevine.
Table 3. Phytotoxicity of metabolites produced by Neofusicoccum species on grapevine.
CodeCompoundAssayConcentrationActivityRef.
1CyclobotryoxideLeaf puncture5.9 mM24.3 ± 1.1 (Area lesions mm2)[17]
2(−)-TerremutinLeaf disk1.3 mM55% (% of necrotic area)[21]
6(+)-epi-SphaeropsidoneLeaf disk1.3 mM47% (% of necrotic area)[21]
8(+)-(6R,7S)-Dia-asperlinLeaf disk0.9 mM33% (% of necrotic area)[21]
9LuteopyroxinDetached leaf2.5 mMWithering and necrotic spots[30]
24(R)-(−)-MelleinLeaf disk
Calli		1.0 mM
2.5 mM		50% (% of necrotic area)
slight partial necrosis		[21]
[22]
25(R)-(−)-3-HydroxymelleinLeaf disk1.0 mM62% (% of necrotic area)[21]
26(3R,4R)-(−)-4-hydroxymelleinLeaf disk1.0 mM34% (% of necrotic area)[21]
27(3R,4S)-(−)-4-hydroxymelleinLeaf disk1.0 mM33% (% of necrotic area)[21]
35Botryosphaerone ALeaf puncture *3.7 mM4.74 (Area lesions mm2)[19]
38Botryosphaerone DLeaf puncture
Leaf puncture *		3.9 mM,
3.9 mM		11.9 (Area lesions mm2)
9.11 (Area lesions mm2)		[17],
[19]
39IsoscleroneLeaf puncture *5.6 mM2.73 (Area lesions mm2)[19]
433,4,5-Trihydroxy-1-tetraloneLeaf puncture *5.2 mM2.13 (Area lesions mm2)[19]
553-MethylcatecholLeaf puncture8.1 mM4.9 (Area lesions mm2)[17]
59p-CresolDetached leaf2.5 mMLow phytotoxicity[30]
61TyrosolLeaf puncture7.2 mM8.3 ± 1.3 (Area lesions mm2)[17]
87LuteoxepinoneDetached leaf2.5 mMWithering and necrotic spots[30]
88–89Luteoethanones A and BDetached leaf2.5 mMLarge necrotic spots, severe shriveling, and distortion of the leaf lamina[18]
90NeoanthraquinoneDetached leaf2.5 mMLarge necrotic spots, severe shriveling and distortion of the leaf lamina[30]
91(±)-NigrosporioneDetached leaf2.5 mMWithering and necrotic spots[30]
* Assays conducted under dark conditions.
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Salvatore, M.M.; Alves, A.; Andolfi, A. Secondary Metabolites Produced by Neofusicoccum Species Associated with Plants: A Review. Agriculture 2021, 11, 149. https://doi.org/10.3390/agriculture11020149

AMA Style

Salvatore MM, Alves A, Andolfi A. Secondary Metabolites Produced by Neofusicoccum Species Associated with Plants: A Review. Agriculture. 2021; 11(2):149. https://doi.org/10.3390/agriculture11020149

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Salvatore, Maria Michela, Artur Alves, and Anna Andolfi. 2021. "Secondary Metabolites Produced by Neofusicoccum Species Associated with Plants: A Review" Agriculture 11, no. 2: 149. https://doi.org/10.3390/agriculture11020149

APA Style

Salvatore, M. M., Alves, A., & Andolfi, A. (2021). Secondary Metabolites Produced by Neofusicoccum Species Associated with Plants: A Review. Agriculture, 11(2), 149. https://doi.org/10.3390/agriculture11020149

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