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Review

Secondary Metabolites from Fungi Microsphaeropsis spp.: Chemistry and Bioactivities

by
Guodong Song
1,
Zhibin Zhang
1,*,
Xuenan Niu
1 and
Du Zhu
1,2,*
1
Key Laboratory of Protection and Utilization of Subtropical Plant Resources of Jiangxi Province, College of Life Science, Jiangxi Normal University, Nanchang 330022, China
2
Key Laboratory of Bioprocess Engineering of Jiangxi Province, College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang 330013, China
*
Authors to whom correspondence should be addressed.
J. Fungi 2023, 9(11), 1093; https://doi.org/10.3390/jof9111093
Submission received: 25 August 2023 / Revised: 29 October 2023 / Accepted: 1 November 2023 / Published: 9 November 2023
(This article belongs to the Special Issue Recent Advances in Fungal Secondary Metabolism)
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Abstract

:
Microsphaeropsis, taxonomically classified within the kingdom fungi, phylum Ascomycota, subphylum Deuteromycotina, class Coelomycetes, order Sphaeropsidales, and family Sphaeropsidaceae, exhibit a ubiquitous distribution across various geographical regions. These fungi are known for their production of secondary metabolites, characterized by both structural novelty and potent biological activity. Consequently, they represent a significant reservoir for the advancement of novel pharmaceuticals. In this paper, a systematic review was present, marking the analysis of secondary metabolites synthesized by Microsphaeropsis reported between 1980 and 2023. A total of 112 compounds, comprising polyketones, macrolides, terpenoids, and nitrogen-containing compounds, were reported from Microsphaeropsis. Remarkably, among these compounds, 49 are novel discoveries, marking a significant contribution to the field. A concise summary of their diverse biological activities was provided, including antibacterial, antitumor, and antiviral properties and other bioactivities. This analysis stands as a valuable reference, poised to guide further investigations into the active natural products derived from Microsphaeropsis and their potential contributions to the development of medicinal resources.

1. Introduction

Microsphaeropsis, taxonomically classified within the phylum Ascomycetes, subphylum Deuteromycotina, class Coelenterata, order Sphaeropsidales, and family Sphaeropsidaceae in the fungal taxonomy [1], are common plant pathogens widely distributed in nature [2]. For a long time, the genus Microsphaeropsis was not accurately recognized, leading to the misplacement of many fungi within the genus Coniothyrium. In 1980, Sutton meticulously elucidated the characteristics of the Microsphaeropsis genus. He subsequently reclassified species previously assigned to the genus Coniothyrium under Microsphaeropsis and renamed the genus [3,4]. Subsequently, additional members of the genus Microsphaeropsis have been unearthed and taxonomically elucidated. As of now, the repository of the Species Fungorum database (https://speciesfungorum.org/Names/Names.asp (accessed on 2 November 2023)) registers a total of 54 species within the genus Microsphaeropsis. It is evident that fungi within the genus Microsphaeropsis exhibit remarkable biodiversity, with a high likelihood of containing structurally novel and biologically active secondary metabolites.
Fungi have been recognized for their remarkable capacity to synthesize secondary metabolites, and the extraction of natural products from fungal secondary metabolites offers significant advantages in terms of yield, economic viability, and environmental sustainability [5,6]. Following the taxonomic redefinition of the Microsphaeropsis genus by Sutton in 1980, various structural categories of compounds, including polyketides, terpenoids, nitrogen-containing compounds, macrolides, and others, were isolated from 2 known and 17 unknown species of Microsphaeropsis, and these demonstrated excellent antibacterial, antifungal, cytotoxic, and other activities (Table 1). This repertoire encompasses numerous structurally novel compounds. However, there exists a current paucity of both domestic and international research focused on the secondary metabolites originating from this genus of fungi. This thesis presents the review of the spectrum of secondary metabolites derived from fungi within the Microsphaeropsis genus, shedding light on their structural diversity and biological activities. This effort not only advances our understanding of these fungal secondary metabolites but also lays the foundation for future exploration and exploitation of the resources within this genus.

2. Types of Chemical Structures

2.1. Polyketones

Polyketones represent a class of secondary metabolites characterized by their exceptionally diverse structures. These compounds are generated through a sequence of Claisen condensation reactions involving short-chain acyl-CoA molecules such as acetyl-CoA and malonyl-CoA. Their distinctive activities have positioned them as a prominent source for both the treatment of human diseases and the development of novel pharmaceuticals. Seventy-six polyketone compounds were found in Microsphaeropsis (Figure 1), encompassing pyranones, furanones, naphthoquinones, anthraquinones, phenylpropanoids, and coumarins. In terms of sheer chemical diversity, polyketones emerge as the most extensively documented natural products among the fungi within the Microsphaeropsis genus.

2.2. Terpenoids

Terpenoids represent a class of natural compounds characterized by their foundational isoprene or isopentane unit structures. They exhibit unparalleled structural diversity and comprise the most extensive group of natural compounds, offering a wide array of activities, including anti-inflammatory, antibacterial, and antitumor properties [32,33]. Seven sesquiterpenes were discovered within Microsphaeropsis (Figure 2), and this collection includes eucalyptus sesquiterpenes, airimo phenolic sesquiterpenes, and sesterterpene.

2.3. Macrolide

Macrolide compounds represent a class of multi-carbon compounds distinguished by the presence of a lactone ring within their molecular structure. They are notable for their pronounced anti-inflammatory, anti-tumor, and antibacterial activities [34]. A comprehensive review of 10 macrolides (Figure 3), comprising two distinct structural types, 10-member macrolides and 16-member macrolides, is provided. These are the first natural-product-bearing three lactone groups in the molecule among the 16-membered macrocyclic antibiotics, showcasing remarkable anti-leukocyte activity.

2.4. Nitrogen Compounds

Nitrogen-containing compounds represent another prevalent and exceptionally diverse class of secondary metabolites. They are distinguished by their intricate cyclic structures and demonstrate substantial biological activities against bacteria, fungi, and tumor cells [35]. This study offers an extensive review of 14 nitrogen-containing compounds, encompassing a range of subtypes (Figure 4), including organic amines alkaloids, pyrrole alkaloids, pyrazine alkaloids, imidazolone alkaloids, indole alkaloids.

2.5. Other Classes

In addition to their primary secondary metabolites, Microsphaeropsis fungi also generate a limited quantity of fatty acids and chlorine-containing compounds (Figure 5). Among these, compound 112 has demonstrated noteworthy antibacterial activity.

3. Biological Activities

Numerous studies have revealed the isolation of a plethora of bioactive compounds from the secondary metabolites of Microsphaeropsis fungi [7,9]. These compounds encompass a wide spectrum of activities, notably including antifungal, antibacterial, cytotoxic, cell adhesion inhibition, antiviral, antimalarial, and antioxidant activities [15,18,31]. Furthermore, some of these compounds exhibit a substantial potential for their development into novel pharmaceuticals.

3.1. Antifungal Activity

Qin et al. (2017) successfully isolated four compounds from the endophyte fungus Microsphaeropsis arundinis PH 30472, which inhabits the plant Panax notoginseng. These compounds comprise a novel isochroman derivative, erythro-2-methyl-5-hydroxy -phenylpropane-7,8-diol (1) and three known compounds: (4S)-4,8-dihydroxy -3,4-dihydro-1(2H)-naphthalen-1-one (2), (4S)-4,6,8-trihydroxy-3,4-dihydro-1(2H)- naphthalen-1-one (3), and chrysogeside D (94). Notably, compounds 3 and 94 were discovered for the first time in Microsphaeropsis. The research team conducted evaluations of the antifungal activity of these compounds. Compound 1 and compound 94 exhibited moderate antifungal activity against A. tenuissima with minimum inhibitory concentrations (MICs) at 64 μg/mL [7].
The novel compound microsphaeropsisin (77), along with the known compounds (R)-mellein (8), (3R,4S)-hydroxymellein (9), (3R,4R)-hydroxymellein (10), and 4,8-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (11), were successfully isolated from the fungus Microsphaeropsis sp. H5-50, which inhabits the marine sponges M. incrustans. Notably, both compounds displayed significant antifungal activity against E. repens and U. violacea in agar diffusion assays [9].
Sommart et al. (2012) isolated nineteen compounds from the endophyte fungus M. arundinis PSU-G18, found within the plant Garcinia hombroniana [15]. Among these compounds, one new modiolin, microsphaerodiolin (110), and seven new phthalides, microsphaerophthalides A-G (29–35), were identified, alongside eleven known compounds (36–44, 93, and 111). Compound 44 exhibited remarkable antifungal activity, with an IC50 value of 8 μg/mL. Additionally, microsphaerophthalides A (29) and microsphaerophthalides E (33) displayed moderate antifungal activity against M. gypseum SH-MU-4 and C. neoformans, both with MIC values of 64 μg/mL. Decaspirone (57), isolated from the endophyte fungus Microsphaeropsis sp. 7291, demonstrated significant antifungal activity against M. violaceum, evidenced by inhibition zone diameters measuring 18 mm [18].
A novel polychlorinated triphenyl diether, microsphaerol (112), was successfully isolated from the endophyte fungus Microsphaeropsis sp. 7820, found inhabiting the plant Salsola oppositifolia. Remarkably, compound 112 exhibited moderate antifungal activity against M. violaceum, resulting in inhibition zone diameters measuring 9 mm [31].
Liu et al. (2020) isolated two novel metabolites, microketides A (74) and microketides B (75), from the fungus Microsphaeropsis sp. RA10-14, and both compounds exhibited significant antifungal activity against Candida albicans, Colletotrichum truncatum, Gloeosporium musarum, and Pestalotia calabae [21]. Microketides A (74) exhibited IC50 values of 1.56 μg/mL, 1.56 μg/mL, 3.13 μg/mL, and 1.56 μg/mL, respectively. Microketides B (75) displayed equal IC50 values of 3.13 μg/mL.

3.2. Antibacterial Activity

Four metabolites, namely microsphaerins A–D (45–48), were isolated from Microsphaeropsis sp. F2076 and Microsphaeropsis sp. F2078. Notably, the four microsphaerins, A, B, C, and D, exhibited significant antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA), with IC50 values of 3 μM, 3 μM, 5 μM, and 1 μM, respectively. To delve deeper into their antibacterial activity, microsphaerins D (48) was selected for further investigation, encompassing Gram-positive and Gram-negative bacteria. Results revealed that it demonstrated moderate antibacterial activity against various Gram-positive bacteria; however, it displayed inactivity against Gram-negative bacteria, except for K. pneumoniae [16].
Five new metabolites, namely palmarumycin M1 (56), palmarumycin M2 (58), papyracillic acid C (61), microsphaeropsins A (78), and microsphaeropsins B (62), were successfully isolated, alongside three known compounds, decaspirone (57), papyracillic acids A (59), and papyracillic acids B (60), from the endophyte fungus Microsphaeropsis sp. 7291, which resides within the plant Pilgerodendron uviferum. Of significance, compounds 56, 57, and 58 exhibited moderate antibacterial activity against B. megaterium, resulting in inhibition zone diameters of 6 mm, 6 mm, and 7 mm, respectively [18].
Krohn et al. (2009) conducted a comprehensive study resulting in the isolation of several metabolites from the endophyte fungus Microsphaeropsis sp. 8875 residing in the plant Lycium intricatum [20], and they isolated three new compounds, microsphaeropsones A-C (64–66), in addition to two known compounds, citreorosein (67) and emodin (68). Moreover, from a Microsphaeropsis sp. 7177 strain sourced from the plant Zygophyllum fortanesii, they identified two new metabolites, 3,4-dihydrofusidienol A (70) and microsxanthone (73), along with three known compounds, fusidienol A (69), 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylic acid methyl ester (71), and methyl 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (72). Remarkably, all these compounds exhibited significant antibacterial activity, particularly against the Gram-negative bacterium E. coli. Microsphaerol (112), derived from the endophyte fungus Microsphaeropsis sp. 7820, displayed moderate antibacterial activity against B. megaterium and E. coli, evidenced by inhibition zone diameters measuring 9 mm and 8 mm, respectively [31].
Two novel metabolites, microketide A (74) and microketide B (75), were successfully isolated from the fungus Microsphaeropsis sp. RA10-14, which inhabits the gorgonian Anthogorgia ochracea from the South China Sea. Both compounds exhibited significant antibacterial and antifungal activities, with a notable emphasis on their antibacterial effects. Specifically, compound 74 demonstrated significant antibacterial activity against B. subtilis, B. megaterium, E. aerogenes, K. rhizophila, and P. aeruginosa, all with equal MIC values of 0.19 μg/mL, mirroring the potency of ciprofloxacin [21]. Ciprofloxacin is used for the treatment of a wide range of infections and has been shown to be active against various Gram-positive and Gram-negative bacteria [36,37,38].
The new isomer, 3′-O-demethylpreussomerin I (16), was isolated alongside seven known compounds from the fungus Microsphaeropsis sp. BCC 3050. This fungal strain was collected from the lichen Dirinaria applanata. The known compounds in this collection include preussomerins E (18), F (19), G (20), H (21), I (17), deoxypreussomerins A (22), and bipendensin (23). Remarkably, all compounds, except compound 23, exhibited activities against M. tuberculosis, and compounds 16, 17, and 18 showed moderate antibacterial activity, with IC50 values of 25 μg/mL, 12.5 μg/mL, and 25 μg/mL, respectively. Compounds 19, 20, 21, and 22 showed significant antibacterial activity, with IC50 values of 3.12 μg/mL, 3.12 μg/mL, 6.25 μg/mL, and 1.56 μg/mL, respectively [12]. Additionally, chrysogeside D (94), sourced from the endophyte fungus Microsphaeropsis arundinis PH 30472, showed moderate antibacterial activity against E. coli [7].
Three novel ent-eudesmane sesquiterpenoids, namely arundinols A (79), B (80), and C (81), were isolated alongside three known compounds from the endophyte fungus M. arundinis E12-2112, which resides within the plant Ulmus macrocarpa. Among the known compounds, one isochroman-1-one, arundinone A (27), a polyoxygenated benzofuran-3(2H)-one dimer, arundinone B (28), and 1β-hydroxy-α-cyperone (82) were identified. Significantly, compound 82 displayed moderate antibacterial activity against S. aureus with an value of 11.4 μg/mL [14].

3.3. Cytotoxic Activity

A new metabolite, (R)-1′-(2,5-dihydroxyphenyl)-1′-oxobutan-3′-ylacetate (4), was isolated, alongside six known compounds, (R)-1-(2,5-dihydroxyphenyl)-3-hydroxybut -anone (5), 1-(2,5-dihydroxyphenyl)-2-buten-1-one (6), (R)-6-hydroxy-2-methyl-4-chrom -anone (7), modiolide D (84), modiolide E (85), and modiolide A (86). These compounds were obtained from the endophyte fungus M. arundinis, residing within the plant Paepalanthus planifolius [8,23]. Additionally, Botero et al. (2020) reported, for the first time, that compound 5 exhibited moderate cytotoxic activity against murine breast adenocarcinoma (LM3), with IC50 values of 36.83 ± 4.86 μg/mL, while compound 6 displayed moderate cytotoxic activity against human breast cancer (MCF-7), with IC50 values of 33.95 ± 3.62 μg/mL [8].
Keusgen et al. (1996) successfully isolated a cerebroside, namely N-2”-hydroxy- 3’E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E,8E-sphingadiene (98), through alterations of the culture medium for the fungus M. olivacea F010 [39]. Remarkably, at a concentration of 2 μg/mL, compound 98 demonstrated significant cytotoxic activity against murine leukemic cells (L1210), achieving an inhibition ratio of 90% [28].
Three novel metabolites, TAN-1496 A (99), C (101), and E (103), in conjunction with two known compounds, TAN-1496 B (100) and D (102), were successfully isolated from the fungus Microsphaeropsis sp. FL-16144. Extensive research has revealed that these compounds act as specific inhibitors of calf thymus Topo I [40]. Notably, even at high concentrations, these compounds did not inhibit the function of Topo II. They exhibited a significant inhibition of the growth of various murine and human tumor cells, including P815 murine mastcytoma, EL4 murine lymphoma, Bl6 murine melanoma, WiDr human colon adenocarcinoma, and A549 human lung carcinoma [29]. Additionally, these compounds displayed activity against Gram-positive bacteria [29].
It has been widely reported that cell adhesion molecules play pivotal roles in numerous physiological and biochemical processes, ranging from cancer [41,42,43] to inflammation [44]. In a remarkable discovery, Hayashi et al. (1995) isolated two new 16-membered macrolides, namely macrosphelide A (87) and macrosphelide B (88), from the fungus Microsphaeropsis sp. FO-5050 [24]. To explore the impact of macrosphelide A and B on cell adhesion, experiments were conducted using the dose-dependently inhibited adhesion of HL-60 cells to human umbilical vein endothelial cells (HUVECs) stimulated with LPS. These compounds exhibited significant cytotoxicity, with IC50 values of 3.5 μM and 36 μM, respectively. Notably, in vitro cell growth assays showed that these compounds had no discernible effect on the growth of cells, including P388 leukemia, human prostate tumor cells, and L929 fibroblast cells, even when administered at a high dose of 200 mg/kg for 5 days [45]. Takamatsu’s (1997) group isolated two more 16-membered macrolide metabolites, macrosphelide C (89) and macrosphelide D (90) from the fungus Microsphaeropsis sp. FO-5050 [25]. Macrosphelide C (89) and macrosphelide D (90) exhibited moderate cytotoxic activity, with IC50 values of 67.5 μM and 25 μM, respectively. Fukami et al. (1998) continued their exploration of the fungus Microsphaeropsis sp. FO-5050 and made further discoveries [10]. They isolated three new metabolites, macrosphelide J (91), macrosphelide K (92), and 6-epi-5’-hydroxymycosporulone (12). Although these compounds displayed cytotoxic activity, their IC50 values exceeded 100 μg/mL. Collectively, these findings underscore the exceptional potential of the fungus Microsphaeropsis sp. FO-5050 as a source of novel macrolides with cytotoxic properties. These substances hold high promise for future development in the treatment of leukemia.
Singh et al. (1994) previously reported that compounds 18, 19, and 20 possess the capability to inhibit Ras farnesyl-protein transferase [46]. Seephonkai et al. (2002) corroborated this finding in their research [12]. Furthermore, compounds 16–21 have demonstrated significant cytotoxicity against a spectrum of cell lines, including human epidermoid carcinoma (KB cells), human breast cancer (BC-1 cells), and African green monkey kidney fibroblast (vero cells). Compound 28, sourced from the endophyte fungus M. arundinis E12-2112, has exhibited moderate cytotoxicity against human bladder carcinoma cells (T24) and human lung carcinoma cells (A549), characterized by IC50 values of 35.4 μg/mL and 81.6 μg/mL, respectively [14].

3.4. Other Biological Activities

Seven known compounds, namely butyrolactone I (49), graphislactone A (50), ulocladol (51), botrallin (52), 2,5-diacetylphenol (53), 7-hydroxy-2,4-dimethyl-3(2H)- benzofuranone (54), and enalin (55), were isolated from the endophyte fungus M. olivacea, which resides within the plant Pilgerodendron uviferum. Remarkably, graphislactone A (50) and botrallin (52) exhibited significant activity against acetylcholinesterase (AChE), characterized by IC50 values of 8.1 μg/mL and 6.1 μg/mL, respectively. However, all these compounds displayed no discernible antibacterial or antifungal activities [17].
Fukami et al. (2000) isolated a novel anti-influenza virus antiviral, known as 10-norparvulenone (76), from the fungi Microsphaeropsis sp. FO-5050 [22]. Interestingly, this compound did not exhibit any discernible antibacterial activity. However, experimental results revealed its remarkable ability to inhibit the replication of the influenza virus A/PR/8/34 strain within Madin-Darby Canine Kidney (MDCK) cells. The outcomes of these experiments were striking: In the absence of the compound, only 27.2% of the cells survived. In contrast, when the compound was introduced at a concentration of 25 μg/mL, cell survival significantly increased to 64.8%. This groundbreaking discovery suggests that compound 76 holds great promise as a novel class of anti-influenza virus drugs, representing a potential breakthrough in the realm of influenza treatment.
Bradykinin, an endogenous peptide, exerts its effects through specific cell receptors, giving rise to a plethora of physiological reactions, including pain, allergic responses, and muscle contractions. Bradykinin antagonists hold the potential to inhibit these physiological reactions, offering prospects for treating conditions such as inflammatory edema, rhinitis, and asthma. In a significant discovery, a novel non-peptide bradykinin-binding inhibitor, L-755,807 (95), was isolated from the endophyte fungus Microsphaeropsis sp. MF6057, found within the plant Prosopis glandulosa. Compound 95 demonstrated an IC50 value of 71 μM in binding to a cloned human B2 receptor with 3H-bradykinin, marking a noteworthy development in the pursuit of potential treatments [26].
Two novel γ-pyrone derivatives, microsphaerones A (96) and microsphaerones B (97), were successfully isolated from the fungus Microsphaeropsis sp. KMPB W-22. Interestingly, neither of these compounds exhibited significant cytotoxicity. Additionally, they displayed either no activity or only moderate activity against S. littoralis and A. salina [27].
Two novel betaenone derivatives (compounds 83 and 104) and three fresh 1,3,6,8-tetrahydroxyanthraquinone congeners (13–15) were successfully extracted from the fungus Microsphaeropsis sp. KMPB W-22. Remarkably, all these compounds, with the exception of compound 104, exhibited moderate inhibitory activity against protein kinases such as PKC, CDK4, and EGF-R, encompassing an IC50 range of 18.5–54.0 μM [11].
From a global vantage point, malaria continues to rank among the foremost causes of human mortality. Consequently, the current paramount emphasis remains on research and the development of targeted pharmaceutical interventions. Seephonkai et al. (2002) first reported on the in vitro activity of preussomerins against Plasmodium falciparum [12]. Compound 16–21 showed significant antiplasmodial activity, with an IC50 range of 0.32–3.44 μg/mL.
Compound 44, sourced from the endophyte fungus M. arundinis PSU-G18, has exhibited significant antiplasmodial activity, boasting an IC50 value of 9.63 μg/mL. Notably, it also demonstrates significant radical scavenging capabilities, with an IC50 value of 0.018 mg/mL [15]. In another remarkable finding, palmarumycin M1 (56), decaspirone (57), and papyracillic acids A (59), all originating from the endophyte fungus Microsphaeropsis sp. 7291, have demonstrated anti-algal activity against C. fusca. Their inhibitory effects are reflected in inhibition zone diameters of 6 mm, 13 mm, and 7 mm, respectively [18]. Similarly, compound 112, derived from the endophyte fungus Microsphaeropsis sp. 7820, has displayed anti-algal activity against C. fusca, characterized by an inhibition zone diameter of 8.5 mm [31]. Additionally, compounds 64–73, apart from 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylic acid methyl ester (71), have demonstrated anti-algal activity against C. fusca [20]. Finally, microketides A (74) and microketides B (75), isolated from Microsphaeropsis sp. RA10-14, have exhibited moderate antiphytoplankton activity against P. helgolandica, showcasing IC50 values of 12.3 μg/mL and 16.8 μg/mL, respectively [21].
Furthermore, several compounds were isolated from fungi within the Microsphaeropsis genus, and their activities have yet to be determined. For instance, Liu et al. (2018) isolated six known metabolites, including butyrolactones I (24), butyrolactones IV (25), aspernolide D (26), fumiquinazolines L (105), fumiquinazolines N (106), and notoamide D (107), from the fungus Microsphaeropsis sp. CF09-11, sourced from marine sediment [13]. It is noteworthy that these compounds (24–26 and 105–107) were obtained from Microsphaeropsis for the first time. In a unique discovery, uncommon methyl-branched unsaturated fatty acids, 10-methyl-9Z-octadecenoic acid (108) and glyceride (109), were isolated from the endophyte fungus M. olivacea, which inhabits the marine sponge Agelus sp. This marks the first report of fungal fatty acids with methyl branches on a cis-double bond [30]. Additionally, three known metabolites, namely massarigenin A (63), papyracillic acids A (59), and papyracillic acids B (60), were isolated from the endophyte fungus Microsphaeropsis sp., originating from the plant Arbutus unedo. Importantly, this research led to the establishment of the absolute configuration of massarigenin A (63) [19].

4. Conclusions

Since Sutton reclassified the genus Microsphaeropsis in 1980, fifty-four different species have been included. Currently, this genus has yielded an impressive array of secondary metabolites, with 112 secondary metabolites reported, of which 49 (41.96%) were identified for the first time. These compounds are distributed across various structural classes, including 76 polyketones (67.86%), 14 nitrogenous compounds (12.5%), 10 macrolides (8.9%), 7 terpenoids (6.25%), and 5 other compounds (4.46%), indicating polyketones are the predominant structural type (Figure 6A). Moreover, a significant proportion (57.89%) of these compounds exhibit notable biological activities, of which 42 compounds (60.6%) demonstrate both antibacterial and antifungal properties, while 21 (37.8%) compounds exhibit antitumor activities. Furthermore, several compounds display distinct activities, including scavenging oxygen-free radicals, algae removal, resistance to aging, and acetylcholinesterase inhibition (Figure 6B). It is important to highlight that many compounds exhibit multiple activities. For instance, compound 44 demonstrates antibacterial, antitumor, and certain oxygen-free radical scavenging activities.
Fungi occupy an exceptionally pivotal role in drug discovery [47]. Many renowned drug molecules, including penicillin and lovastatin, have originated from fungal sources [48]. However, the challenge of unearthing novel compounds of exceptional activity and expanding the repertoire of known compound activities remains unresolved. Given the abundance and significant innovation rate (41.96%) of secondary metabolites, Microsphaeropsis can be used as a potential repository for exploiting secondary metabolites. Accordingly, the following recommendations were proposed: (i) Employ non-directional activation strategies to activate the biosynthesis of secondary metabolites, such as the OSMAC (one strain many compounds) strategy [49], co-culture strategy [50], and epigenetic regulation strategy [51]. (ii) Harness targeted activation strategies to activate numerous dormant gene clusters within fungal genomes, such as target sequence promoter replacements [52], transcription regulatory factor knockouts [53], the heterologous expression of biosynthetic gene clusters [54], DNA-assembly technology [55], and ribosome engineering [56]. However, the genomic information of Microsphaeropsis has not been reported in the literature so far. Thus, whole gene sequencing and analysis will be the focus of further work. (iii) Expand the scope of activity screening of existing compounds and delve into their mechanism of action to verify their potential for pharmaceutical applications. For instance, microbetides A (74), a novel polyketone compound, demonstrates remarkable antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, with an IC50 of 0.19 μg/mL, comparable to ciprofloxacin. Polyketone 10-norparvulone (76) exhibits the potential to effectively inhibit virus replications, positioning it as a promising candidate for a new anti-influenza drug. Macrolide compounds like macrosphelide A (87) and macrosphelide B (88), characterized by their unique chemical structures and cytotoxicity against leukemia, hold promise as novel anticancer drugs.

Author Contributions

Z.Z. and D.Z. conceived and revised this article; G.S. and X.N. conducted the literature analysis; and G.S. wrote the original draft of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82160671, 31960078).

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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Jof 09 01093 g001aJof 09 01093 g001b
Figure 1. Chemical structures of polyketone compounds 1–76.
Figure 1. Chemical structures of polyketone compounds 1–76.
Jof 09 01093 g001aJof 09 01093 g001b
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Figure 2. Chemical structures of terpenoid compounds 77–83.
Figure 2. Chemical structures of terpenoid compounds 77–83.
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Figure 3. Chemical structures of macrolide compounds 84–93.
Figure 3. Chemical structures of macrolide compounds 84–93.
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Figure 4. Chemical structures of nitrogen compounds 94–107.
Figure 4. Chemical structures of nitrogen compounds 94–107.
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Figure 5. Chemical structures of compounds 108–112 of other classes.
Figure 5. Chemical structures of compounds 108–112 of other classes.
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Figure 6. Structural classification (A) and activity classification (B) of secondary metabolites of Microsphaeropsis spp.
Figure 6. Structural classification (A) and activity classification (B) of secondary metabolites of Microsphaeropsis spp.
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Table 1. Summary of secondary metabolites of Microsphaeropsis spp.
Table 1. Summary of secondary metabolites of Microsphaeropsis spp.
No.Chemical NameSourceBioactivities/InactivityRef.
1Erythro-2-methyl-5-hydroxyphenylpropane-7,8-diolM. arundinis PH 30472 Antifungal activity against Alternaria. tenuissima[7]
2(4S)-4,8-dihydroxy-3,4-dihydro-1(2H)-naphthaln-1-oneInactive
3(4S)-4,6,8-trihydroxy-3,4-dihydro-1(2H)-naphthalen-1-oneInactive
4(R)-1′-(2,5-dihydroxyphenyl)-1′-oxobutan-3′-ylacetateM. arundinisInactive[8]
5(R)-1-(2,5-dihydroxyphenyl)-3-hydroxybutanoneAnti-inflammatory activity and cytotoxicity activity against LM3
61-(2,5-dihydroxyphenyl)-2-buten-1-oneAnti-inflammatory activity and cytotoxicity activity against LM3
7(R)-6-hydroxy-2-methyl-4-chromanoneInactive
8(R)-melleinMicrosphaeropsis sp. H5-50Antifungal activity against Eurotium repens[9]
9(3R,4S)-hydroxymelleinAntifungal activity against Ustilago violacea
10(3R,4R)-hydroxymelleinAntifungal activity against E. repens and U. violacea
114,8-dihydroxy-3,4-dihydro-2H-naphthalen-1-oneAntifungal activity against E. repens and U. violacea
126-ep-i 5′-hydroxymycosporuloneMicrosphaeropsis sp. FO-5050Cytotoxicity activity against HL-60[10]
13–151,3,6,8-tetrahydroxyanthraquinone congennersMicrosphaeropsis sp. KMPB W-22Inhibited protein kinases activity (PKC, CDK 4, and EGF-R)[11]
163′-O-demethylpreussomerin IMicrosphaeropsis sp. BCC 3050Antibacterial activity and antiplasmodial activity against plasmodium falciparum and cytotoxicity activity against KB, BC-1, and vero cells [12]
17Preussomerin I-
18Preussomerin E-
19Preussomerin F-
20Preussomerin G-
21Preussomerin H-
22Deoxypreussomerin AAntibacterial activity and antiplasmodial activity against p. falciparum
23BipendensinInactive
24Butyrolactones IMicrosphaeropsis sp. CF09-11Inactive[13]
25Butyrolactones IVInactive
26Aspernolide DInactive
27Arundinone AM. arundinis E12-2112Inactive[14]
28Arundinone BCytotoxicity activity against T24 and A549
29Microsphaerophthalides AM. arundinis PSU-G18Antifungal activity against Microsporum gypseum SH-MU-4, and Cryptococcus neoformans[15]
30Microsphaerophthalides BInactive
31Microsphaerophthalides CInactive
32Microsphaerophthalides DInactive
33Microsphaerophthalides EAntifungal activity against Microsporum gypseum SH-MU-4 and Cryptococcus neoformans
34Microsphaerophthalides FInactive
35Microsphaerophthalides GInactive
36Deoxycyclopaldic acidInactive
375,7-dihydroxy-4,6-
dimethyl-1(3H)-isobenzofuranone		Inactive
385-hydroxy-7-methoxy-4-(methoxymethyl)-6-methylisobenzofuran-1(3H)-oneInactive
395-hydroxy-7-methoxy-4,6-dimethylphthalideInactive
407-methoxy-3,4,5,6-tetramethylphthalideInactive
41SclerinInactive
426-hydroxy-2-methyl-4-chromanoneInactive
43Sclerotinin AInactive
441-(2,5-dihydroxyphenyl)-2-buten-1-oneAntifungal activity against M. gypseum SH-MU-4, antiplasmodial activity against P. falciparum, and radical scavenging potency
45Microsphaerins AMicrosphaeropsis sp. F2076Antibacterial activity against MR31SA[16]
46Microsphaerins B-
47Microsphaerins CMicrosphaeropsis sp. F2078-
48Microsphaerins D-
49Butyrolactone I Microsphaeropsis olivaceaInactive[17]
50Graphislactone AActivity against acetylcholinesterase (AChE)
51Ulocladol Inactive
52Botrallin Activity against AChE
532,5-diacetylphenol Inactive
547-hydroxy-2,4-dimethyl-3(2H)-benzofuranoneInactive
55Enalin Inactive
56Palmarumycin M1Microsphaeropsis
sp. 7291		Antibacterial activity against Bacillus megaterium, and antialgal activity against Chlorella fusca[18]
57DecaspironeAntibacterial activity against B. megaterium and Microbotryum violaceum, and antialgal activity against C. fusca
58Palmarumycin M2Antibacterial activity against B. megaterium
59Papyracillic acid A Inactive
60Papyracillic acid BInactive
61Papyracillic acid CInactive
62Microsphaeropsins B Inactive
63Massarigenin A Microsphaeropsis sp.Inactive[19]
64Microsphaeropsones AMicrosphaeropsis sp. 8875 Antibacterial activity against Escherichia coli and B. megaterium, and antialgae activity against C. fusca[20]
65Microsphaeropsones BAntibacterial activity and antialgae activity against C. fusca
66Microsphaeropsones CAntibacterial activity against E. coli and B. megaterium, and antialgae activity against C. fusca
67CitreoroseinAntibacterial activity against E. coli, B. megaterium, and M. violaceum, and antialgae activity against C. fusca
68EmodinAntibacterial activity and antialgae activity against C. fusca
69Fusidienol AMicrosphaeropsis sp. 7177Antibacterial activity against E. coli, B. megaterium, and M. violaceum, and antialgae activity against C. fusca
703,4-dihydrofusidienol AAntibacterial activity and antialgae activity against C. fusca
718-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylic acid methyl esterAntibacterial activity against E. coli and B. megaterium, and antialgae activity against C. fusca
72Methyl 3,8-dihydroxy-6-methyl-9-oxo-9H-xanth-
ene-1-carboxylate		Antibacterial activity and antialgae activity against C. fusca
73MicroxanthoneAntibacterial activity and antialgae activity against C. fusca
74Microketides AMicrosphaeropsis sp. RA10-14Antibacterial activity against pseudomonas aeruginosa, Nocardia brasiliensis, B. anthraci, and Kocuria rhizophila, and antiphytoplankton activity[21]
75Microketides B-
7610-NorparvulenoneMicrosphaeropsis sp. F0-5050Anti-influenza virus against A/PR/8/34[22]
77MicrosphaeropsisinMicrosphaeropsis sp. H5-50Antifungal activity against E. repens and U. violacea[9]
78Microsphaeropsins AMicrosphaeropsis
sp. 7291		Antialgal activity against C. fusca[18]
79Arundinols AM. arundinis E12-2112Inactive[14]
80Arundinols BInactive
81Arundinols CInactive
821β-hydroxy-α-cyperoneAntibacterial activity against Staphylococcus aureus
83Betaenone derivativeMicrosphaeropsis sp. KMPB W-22Inhibited protein kinases activity (PKC, CDK 4, and EGF-R)[11]
84Modiolide DM. arundinisInactive[23]
85Modiolide EInactive
86Modiolide AInactive
87Macrosphelide AMicrosphaeropsis sp. FO-5050Cytotoxicity activity against HL-60[24]
88Macrosphelide B-
89Macrosphelide C-[25]
90Macrosphelide D-
91Macrosphelide J-[10]
92Macrosphelide K-
93ModiolideM. arundinis PSU-G18Inactive[15]
94Chrysogeside DM. arundinis PH 30472Antifungal activity against A. tenuissima[7]
95L-755, 807Microsphaeropsis sp. MF6057Cell adhesion inhibition activity[26]
96Microsphaerones AMicrosphaeropsis sp. KMPB W-22Insecticidal activity against Spodoptera littoralis and Artemia salina[27]
97Microsphaerones B-
98N-2”-hydroxy-3’Eoctedecenoyl-1-O-β-D-glucopy-ranosyl-9-methyl-4E,8E-sphingadieneM. olivacea F010Cytotoxic activity against L1210[28]
99TAN-1496 AMicrosphaeropsis sp. FL-16144Cytotoxicity activity against P815 murine mastcytoma and A59 human lung carcinoma[29]
100TAN-1496 B-
101TAN-1496 C-
102TAN-1496 D-
103TAN-1496 E-
104Betaenone derivativeMicrosphaeropsis sp. KMPB W-22Inactive[11]
105Fumiquinazolines LMicrosphaeropsis sp. CF09-11Inactive[13]
106Fumiquinazolines NInactive
107Notoamide DInactive
10810-methyl-9Z-octadecenoic acidMicrosphaeropsis olivaceaInactive[30]
109GlycerideInactive
110MicrosphaerodiolinM. arundinis PSU-G18Inactive[15]
111ModiolinInactive
112MicrosphaerolMicrosphaeropsis sp. 7820Antibacterial activity against E. coli and B. megaterium[31]
Note: “-”means the same as above.
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Song, G.; Zhang, Z.; Niu, X.; Zhu, D. Secondary Metabolites from Fungi Microsphaeropsis spp.: Chemistry and Bioactivities. J. Fungi 2023, 9, 1093. https://doi.org/10.3390/jof9111093

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Song G, Zhang Z, Niu X, Zhu D. Secondary Metabolites from Fungi Microsphaeropsis spp.: Chemistry and Bioactivities. Journal of Fungi. 2023; 9(11):1093. https://doi.org/10.3390/jof9111093

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Song, Guodong, Zhibin Zhang, Xuenan Niu, and Du Zhu. 2023. "Secondary Metabolites from Fungi Microsphaeropsis spp.: Chemistry and Bioactivities" Journal of Fungi 9, no. 11: 1093. https://doi.org/10.3390/jof9111093

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