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Review

Pestalotiopsis Diversity: Species, Dispositions, Secondary Metabolites, and Bioactivities

by
Chu Wu
1,*,
Yun Wang
2 and
Yujie Yang
1
1
College of Horticulture & Gardening, Yangtze University, **gzhou 434025, China
2
College of Life Sciences, Yangtze University, **gzhou 434025, China
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(22), 8088; https://doi.org/10.3390/molecules27228088
Submission received: 29 August 2022 / Revised: 23 October 2022 / Accepted: 29 October 2022 / Published: 21 November 2022
(This article belongs to the Special Issue Bioactive Compounds in Food Bioscience and Pharmacology)
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Abstract

:
Pestalotiopsis species have gained attention thanks to their structurally complex and biologically active secondary metabolites. In past decades, several new secondary metabolites were isolated and identified. Their bioactivities were tested, including anticancer, antifungal, antibacterial, and nematicidal activity. Since the previous review published in 2014, new secondary metabolites were isolated and identified from Pestalotiopsis species and unidentified strains. This review gathered published articles from 2014 to 2021 and focused on 239 new secondary metabolites and their bioactivities. To date, 384 Pestalotiopsis species have been discovered in diverse ecological habitats, with the majority of them unstudied. Some may contain secondary metabolites with unique bioactivities that might benefit pharmacology.

1. Introduction

As human society entered a new century, many new problems have to be faced, such as global warming, public health, and food crisis. Especially, novel coronavirus burst in 2020 spring caused a severe effect on global public health and the world economy. More effective novel medications will be investigated to respond to emerging public health challenges. Many bioactive components were already isolated and identified from plants, animals, bacteria, and fungi. Because of the great numbers of bacteria and fungi and their various habitats, they are important sources of bioactive components. Subramanian and Marudhamuthus (2020) [1] isolated and identified the endophytic bacteria, such as Bacillus flexus (DMTMMB08), Bacillus licheniforms (DMTMMB10), and Oceanobacillus picturae (DMTMMB24) from marine macroalgae Sargassum polycystum and Acanthaphora specifera in the benthic region of the Gulf of Mannar, and found that they are taxol-producing. The endophytic fungus Taxomyces andreanae was isolated from the outer bark of Taxus brevifolia and was first found to have the ability to produce taxol in a culture medium, at approximately 24–25 ng/L [2]. Since then, a great number of taxol-producing fungi, acting as endophytic fungi, have been isolated and identified, such as the endophytic fungus Chaetomella raphigera from a medicinal plant, Terminalia arjuna [3], the endophytic fungus Epicoccum nigrum TXB502 [4], and the endophytic fungus Penicillium polonicum from Ginko biloba [5]. Among them, Pestalotiopsis species have been widely studied. The fungal genus Pestalotiopsis was first established by Steyaert R. L. [6]. Since then, many Pestalotiopsis species have been isolated and identified. To date, 384 Pestalotiopsis species are listed in the Index Fungorum (http://www.indexfungorum.org/Names/Names.asp, assessed on 1 August, 2022). All the described species in the Pestalotiopsis genus are differentiated primarily on morphological characteristics of conidia, conidiogenesis, teleomorph, and host associations. In addition, the presence or absence of basal and apical appendages can be used as additional taxonomic characters for identifying Pestalotiopsis species. They are widely distributed in tropical and temperate regions [7,8,9,10]. As early as 1996, taxol was first isolated and identified in Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana [11]. Besides Pestalotiopsis microspora [12,13], some Pestalotiopsis species were also found to produce taxol, such as Pestalotiopsis mangiferae [14], Pestalotiopsis pauciseta [15], Pestalotiopsis breviseta [16,17], Pestalotiopsis terminaliae [18], and Pestalotiopsis hainanensis [19]. Pestalotiopsis microspora was found to produce between 50 and 1487 ng/L taxol, indicating that taxol production could be achieved at a higher concentration; however, the production was found unstable due to different fungal strains of P. microspora [20].
Since taxol discovery in P. microspora, several other secondary metabolites were isolated and identified from Pestalotiopsis species, and their bioactivities were tested. These secondary metabolites possess several bioactivities, such as anticancer, antifungal, antibacterial, antivirus, and insecticide. Yang XL et al. [21] and Xu J et al. [10] summarized secondary metabolites from Pestalotiopsis species. Although Helaly et al. [22] and Becker and Stadler [23] recently summarized secondary metabolites from the order Xylariales, to which the family Sporocadaceae belongs (Pestalotiopsis is a genus of ascomycete in the family Sporocadaceae), they did not focus on these secondary metabolites from the genus Pestalotiopsis. In this review, we summarize recent advances in secondary metabolites isolated and identified from Pestalotiopsis species. Our goal is to encourage the use of these secondary metabolites and the discovery of new Pestalotiopsis metabolites.

2. Habitat and Functional Diversity of Pestalotiopsis Species

Pestalotiopsis species reside in various habitats, including oceans, rivers, lakes, air, soil, and different plant tissues. For instance, Pestalotiopsis submerses, as a root endophytic fungus, were identified in the roots of plants residing in wetlands near ravine areas with elevations of 1150 and 1775 m [24]. The fungus lives in the roots of Equisetum sp., fern, and Lyonia ovalifolia, yet the occurrence frequency is low (12.5%). Pestalotiopsis species were isolated in the outside air of all four child daycare centers tested by Aydogdu and Asan [25]; however, they did not discover these fungi in the indoor air of these child daycare centers. Some Pestalotiopsis species come from the marine environment, such as Pestalotiopsis neglecta [26,27], Pestalotiopsis heterocornis [28,29,30,31], Pestalotiopsis vaccinii [32], Pestalotiopsis sydowiana [33], and other Pestalotiopsis sp. [34,35,36,37]. Pestalotiopsis papuana CBS 331.96 and Pestalotiopsis humus CBS 336.97, on the other hand, were discovered in soil [8]. Astonishingly, Pestalotiopsis hainanensis was identified from the dermatitic scurf of a giant panda (Ailuropoda melanoleuca) [19] and Pestalotiopsis sp. HC02 resides in Chondracris rosee gut [38]. Pestalotiopsis ssp. was also identified as an entomopathogenic fungus on Hemiberlesia pitysophila, an extremely harmful exotic insect in Pinus forests [39]. Thus, the isolate is promising for the biocontrol of H. pitysophila. In addition, Pestalotiopsis species might be related to human diseases. For example, Pestalotiopsis clavispora was identified from a patient’s cornea with recurrent keratitis [40].
In their respective habitats, Pestalotiopsis species show different ecological functions. Pestalotiopsis species, as plant endophytic or saprophytic fungi, reside in other plant tissues, such as bark [41], stems [42], twigs [43], roots [24], leaves [44,45,46,47,48], flowers [49,50], and fruits [51]. As saprophytic fungi, they cause various plant diseases, such as blight diseases in leaves and twigs [43,50,52,53,54,55], leaf necrosis [44], leaf spots [46], fruit rot [51], dry flower disease [56], dieback disease [57,58,59], canker [58,60,61], and even postharvest diseases [62]. Sometimes, Pestalotiopsis species cause destructive diseases. For example, Pestalotiopsis samarangensis was harmful to Syzygium samarangense in Thailand [63]. Some Pestalotiopsis species act as an endophyte or a saprobe in different plant species. For example, P. microspora causes leaf spots in blueberry (Vaccinium corymbosum L.) [46], leaf blight of loquat (Eriobotrya japonica) [64], and leaf blight of Japanese yew (Taxus cuspidate) [65]; however, the fungus more often acts as an endophyte [66,67,68]. Therefore, Pestalotiopsis species play a variety of ecological roles.

3. New Secondary Metabolites in Pestalotiopsis Species

In 2012, it was estimated that 196 secondary metabolites had been encountered in the Pestalotiopsis genus [21]. New secondary metabolites were isolated and identified in the recent decade, and their bioactivities were tested (Table 1). We compared the compounds in the literature published after 2014 with those listed by Yang X-L et al. [21] and Xu J et al. [10] and came up with the following list of novel compounds listed below.

3.1. Pestalotiopsis diploclisia

The marine fungus P. diploclisia (BCC 35283) produces two new hydroquinones bearing a 1,3-enyne moiety, pestalotioquinols G (1) and H (2) [73]. P. microspora has pestalotioquinol A (3) and B (4), and the two compounds are neuroprotective [121]. Furthermore, 1–3 μM pretreatment of pestalotioquinols A (3) and B (4) rescued nerve growth factor-differentiated neuronal PC12 cells from peroxynitrite-induced cytotoxicity, and their protective activity was sustained after removing each compound from the medium; thus, the two compounds (3 and 4) exhibited relatively high neuroprotective effects. In addition, Pestalotioquinol A (3) displayed antimalarial activity against Plasmodium falciparum K1 with an IC50 value of 19.0 μM. In comparison, pestalotioquinol G (1) showed weak cytotoxic activity against Vero cell lines with an IC50 value of 47.9 μM [73].
Molecules 27 08088 i001
P. diploclisia also produces the compound scylatone (5) [73]. Scylatone (5) is one of the melanin biosynthesis intermediates. P. microspora and Pestalotiopsis fici were reported to produce melanin pigment [13,84,90,114,116]. Melanin biosynthesis is complex in fungi, and some fungi have more than one biosynthesis pathway for melanins [185]. Melanization in mycelia and appressoria plays crucial roles in the protection of pathogens from antibiotic stressors and the pathogenicity or interaction with host plants [185,186], and melanin is essential not only for the protection of spores from biotic and abiotic stresses but also structural spore development [84]. Thus, scylatone and melanin are related to the infection of host plants.
Molecules 27 08088 i002

3.2. Pestalotiopsis disseminate

P. disseminate produces disseminins A-E (6–10) and spiciferones D (11) and E (12) [75]. Disseminins A-E (6–10) showed no activity against Aspergillus flavus, Escherichia coli, or Candida albicans at 100 μg/disk [75]. These compounds are synthesized via the pathway shown in Figure 1 [75]:
Spiciferone A (13) and other congeners (14–21) were also isolated and identified in Cadophora luteo-olivacea collected from Port Lockroy on the Antarctic peninsula, endophytic fungus Phoma betae collected from desert plants in West China [187,188], and Cochlioholus spicifer [12]. Spiciferone A (13) is a major phytotoxin to cotyledons of wheat (Triticum aestivum L. cv. Ushio-komugi), and spiciferone C (20) was less phytotoxic to wheat cotyledons than spiciferone A (13), while spiciferone B (19) was not phytotoxic, and dihydrospiciferone A (21) was as active as spiciferone A (13) [12]. Hwang et al. [75] did not observe that spiciferones D (9) and E (10) showed activity against Staphylococcus aureus, Bacillus subtilis, E. coli, and C. albicans at 50 μg/disk. Spiciferone A (13), spiciferol A (14), dihydrospiciferol A (15), spiciferone F (16), and dihydrospiciferone A (21) showed no activity against methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), B. subtilis, Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, C. neoformans, and C. albicans. These five compounds also showed no cytotoxicity against LOX IMVI (melanoma) and SF-295 (glioblastoma) human cancer cell lines [187].
Molecules 27 08088 i003

3.3. Pestalotiopsis fici

P. fici, Pestalotiopsis guepinii, and Pestalotiopsis theae produce ficipyrone A (22) and pestheic acid (i.e., dihidromaldoxin) (23) [78,82,98,166]. Xu X et al. [82] proposed a biosynthesis pathway of pestheic acid. The two compounds showed moderate inhibition of respiratory syncytial virus (IC50 values ranging from 45.00 ± 0.98 to 259.23 ± 2.36 µM) [166]. Sousa et al. [98] assessed the cytotoxic, cytostatic, and genotoxic effects of pestheic acid (23) in a gastric adenocarcinoma cell line (PG100). Their results showed a decrease in clonogenic survival. Pestheic acid (23) also significantly increased both micronucleus and nucleoplasmic bridge frequency. However, they observed no changes in cell cycle kinetics or apoptosis induction. Thus, they considered that pestheic acid (23) was not an active anticancer compound under these conditions, because the minimal inhibitory concentration was high.
Molecules 27 08088 i004
Pestaloficins (24–28) were isolated and identified in P. fici and other Pestalotiopsis sp. [88,189]. In addition, Guo and Zou [190] discovered pestaloficin C (26) in the plant endophytic fungus Monosporascus eutypoides. However, none of the studies focused on the bioactivities of these substances, so their bioactivities need to be tested.

3.4. Pestalotiopsis foedan

(−)-(4S,8S)-foedanolide (29) and (+)-(4R,8R)-foedanolide (30), a pair of new spiro-γ-lactone enantiomers, were isolated from the fermentation broth of the plant endophytic fungus P. foedan [94]. The two compounds showed moderate activities against HeLa cells, lung adenocarcinoma cell line A-549, U-251, HepG2, and MCF-7 tumor cell lines. The IC50 values of (−)-(4S, 8S)-foedanolide (29) against these tumor cell lines were 15.8, 296.0, 159.0, 22.8, and 70.2 μg/mL, respectively; the IC50 values of (+)-(4R,8R)-foedanolide (30) against these tumor cell lines were 5.4, 67.9, 53.0, 19.0, and 20.8 μg/mL, respectively [94].
Yang XL et al. [21] and Xu J et al. [10] introduced some sesquiterpenes, diterpenes, and triterpenes, but not monoterpenes. A new monoterpene lactone, (1R,4R,5R,8S)-8-hydroxy-4,8-dimethyl-2-oxabicyclo [3.3.1]nonan-3-one (31), and (2R)-2-[(1R)-4-methylcyclohex-3-en-1-yl]propanoic acid (32), were isolated from the liquid culture of the plant endophytic fungus P. foedan [95]. Both compounds (31 and 32) exhibited strong antifungal activities against the two pathogens, Botrytis cinerea and Phytophthora nicotianae, with MIC values of 3.1 and 6.3 μg/mL, respectively, which are comparable to those of the known antifungal drug ketoconazole. The compound (32) also showed modest antifungal activity against C. albicans with a MIC value of 50 μg/mL [95].
Molecules 27 08088 i005

3.5. Pestalotiopsis guepinii

P. guepinii is the fungal causal pathogen of hazelnut (Coryus avellana) in Turkey. P. guepinii produced phytotoxic α-pyrones, including 6-(1-hydroxypentyl)-4-methoxy-pyran-2-one (33), derivatives (34, 35, 37, 38) of the compound 33, and 6-pentyl-4-methoxy-pyran-2-one (36) [99]. None of these compounds (33–38) showed antibiotic activities against B. subtilis and Geotrichum candidum when tested up to 100 μg per diskette [99].
Molecules 27 08088 i006

3.6. Pestalotiopsis heterocornis

Heterocornols A-L (39–50), methyl-(2-formyl-3-hydroxyphenyl) propanoate (51), cladoacetal A (52), xylarinol A (53), agropyrenol (54), vaccinol G (55), (R)-3-hydroxy-1-[(R)-4-hydroxy-1,3-dihydroisobenzofuran-1-yl]butan-2-one (56), and (R)-3-hydroxy-1-[(S)-4-hydroxy-1,3-dihydroisobenzo-furan-1-yl]butan-2-one (57) were isolated and identified in the marine sponge-derived P. heterocornis [29]. Heterocornols A-C (39–41), Heterocornols F-H (44–46), methyl-(2-formyl-3-hydroxyphenyl) propanoate (51), agropyrenol (54), and vaccinol G (55) showed cytotoxic activities against four human cancer cell lines with IC50 values of 15–100 μM. These also showed antibacterial activities against Gram-positive bacteria S. aureus and B. subtilis with MIC values ranging from 25 to 100 mg/mL [30]. In addition, these compounds, heterocornol C (41), heterocornol G (45), agropyrenol (54), and vaccinol G (55), exhibited weak antifungal activities against Candida parapsilosis and C. neoformans with MIC values of 100 μg/mL [30].
Molecules 27 08088 i007
Lei H et al. [28] also isolated and identified heterocornols M and N (58, 59) and a pair of epimers, heterocornols O and P (60, 61), in P. heterocornis. The four compounds (58–61) showed cytotoxic activities against four human cancer cell lines (BGC-823, Ichikawa, HepG2, 7860) with IC50 values of 20.4–94.2 µM.
Molecules 27 08088 i008
In P. heterocornis, pestaloisocoumarins A and B (62, 63), gamahorin (64), one sesquiterpenoid degradation product, isopolisin B (65), and one furan derivative, pestalotiol A (66), were also isolated and identified [30]. Pestaloisocoumarins A and B (62, 63) and gamahorin (64) exhibited antibacterial activities against Gram-positive bacteria S. aureus and B. subtilis with MIC values ranging from 25 to 100 µg/mL. The three isocoumarins (62, 63, 64) showed weak antifungal activities against C. albicans, Candidad parapsilosis, and C. neoformans with MIC values of 100 µg/mL. Natural isocoumarins were studied in terms of sources, structural styles, biosynthesis, and biological activity by Shabir et al. [191] and Noor et al. [192], who also gave some relevant information. A mixture of pestalalactone atropisomer A/B (67, 68) showed moderate cytotoxic activities against four human cancer cell lines (BGC-823, H460, PC-3, SMMC-7721) with IC50 values 0f 6.8–87.7 μM, while compounds 62–66 did not exhibit an obvious inhibition effect against the cancer lines at 100 μM [30].
Molecules 27 08088 i009

3.7. Pestalotiopsis humus

Pestynol (69) and pestiocandin (70) were isolated and identified in P. humus FKI-7473 using multidrug-sensitive yeast [102,103]. Pestynol (69) was weakly cytotoxic against three floating cell lines (Jurkat, HL60, and THP-1 cells) and two adherent cell lines (HT29 and A549 cells), with IC50 values of 84, 19, 61, 83, and 92 μM, respectively, and the other three adherent cell lines (HeLa S3, H1299, and Panc1 cells) were not affected at 100 μM of pestynol (69) [102]. Pestiocandin (70) showed moderate or weak growth inhibition against Gram-positive bacteria (S. aureus, B. subtilis, Micrococcus luteus, and Mycobacterium smegmatis), Gram-negative bacteria (Xanthomonas oryzae pv. oryzae and Proteus vulgaris), yeasts (Saccharomyces cerevisiae BY25929 and S. cerevisiae 12geneΔ0HSR-iERG6), and a filamentous fungus (Mucor racemosus), with MIC values of 8–256 μg/mL [103]. The compound (70) did not exhibit effects on Gram-negative bacteria (B. subtilis, K. pneumoniae, and P. aeruginosa) and yeasts (C. albicans, S. cerevisiae KF237, and S. cerevisiae BY4741), with MIC values of more than 256 μg/mL.
Molecules 27 08088 i010

3.8. Pestalotiopsis karstenii

Two oxysporone derivatives, pestalrone A (71) and pestalrone B (72), were isolated and characterized in the endophytic plant fungus P. karstenii isolated from stems of Camellia sasanqua and foliar endophytic fungus Pestalotiopsis zonata [42,184]. Pestalrone A (71) had no inhibitory effects on the five human tumor cell lines (HeLa, U-251, A549, HepG2, and MCF-7). At the same time, pestalrone B (72) showed significant activities against the three human tumor cell lines (HeLa, HepG2, and U-251) with IC50 values of 12.6, 31.7, and 5.4 µg/mL, respectively. However, this compound (72) did not show noticeable cytotoxic activities against cell lines A549 and MCF-7 [42]. In addition, pestazonatic acid (73) was isolated and identified in P. zonata [184], yet its bioactivity was not evaluated.
Molecules 27 08088 i011

3.9. Pestalotiopsis mangiferae

A phenolic compound, 4-(2,4,7-trioxa-bicyclo [4.1.0]heptan-3-yl) phenol (74), was isolated and characterized from the endophytic fungus P. mangiferae associated with Mangifera indica [107]. The compound (74) showed appreciable antibacterial and antifungal activities against B. subtilis, K. pneumoniae, C. albicans (MIC of 0.039 mg/mL), B. subtilis, and M. luteus (MIC of 1.25 mg/mL) followed by P. aeruginosa (MIC of 5.0 mg/mL).

3.10. Pestalotiopsis microspora

Yang XL et al. [21] and Xu J et al. [10] introduced novel sesquiterpenes. Three new sesquiterpenes, (+)-dendocarbin L (75), (+)-sydonic acid (76), and (+)-sydowic acid (77), were isolated from the mycelium of the endophytic fungus P. microspora associated with the stem of Artocarpus heterophyllus [68]. Their cytotoxicity was evaluated on murine leukemia P-388 cells, with IC50 values of 18.78, 20.30, and 2.56 μg/mL for (+)-dendocarbin L (75), (+)-sydonic acid (76), and (+)-sydowic acid (77), respectively. Thus, among the three compounds (75, 76, 77), (+)-sydowic acid (77) exhibits the most potential to inhibit murine leukemia P-388 cells.
Molecules 27 08088 i012
Yang et al. [21] presented pestalotioprolides A and B. New analogs were isolated and identified as well. Pestalotioprolides C-H (78–83) and 7-O-methylnigrosporolide (84) were isolated from a mangrove-derived endophytic fungus P. microspora [118]. The four compounds, 7-O-methylnigrosporolide (84), pestalotioprolide D (79), pestalotioprolide E (80), and pestalotioprolide F (81), showed significant cytotoxicity against the murine lymphoma cell line L5178Y with IC50 values of 0.7, 5.6, 3.4, and 3.9 μM, respectively, while pestalotioprolide E (80) exhibited potent activity against the human ovarian cancer cell line A2780 with an IC50 value of 1.2 μM. Interestingly, co-culture of P. microspora with Streptomyces lividans caused an approximately 10-fold enhanced accumulation of pestalotioprolide E (80) and pestalotioprolide F (81), compared to axenic fungal controls [118]. The enhanced accumulation is beneficial for the formation of pestalotioprolide E (80) and pestalotioprolide F (81), and attention should be directed to associated molecular pathways.
In addition, nigrosporolide (85) and 4,7-dihydroxy-13-tetradeca-2,5,8-trienolide (86) were isolated in P. microspora and the mold Nigrospora sphaerica [118,193]. The two compounds (85 and 86) showed weak bioactivities against lymphoma cell line L5178Y with an IC50 value of 21 μM, while they exhibited no biological activities against ovarian cancer cell line A2780 with an IC50 value of more than 40 μM [118]. Furthermore, Harwooda et al. [193] reported that nigrosporolide (85) caused 100% inhibition in the growth of etiolated wheat coleoptile sections at 10−3 M; however, it showed no effect at lower concentrations. Since auxins have a significant impact on plant development, nigrosporolide (85) could be analyzed as a new component in the auxin signaling pathway, such as the TOR kinase found via rapamycin produced by the soil bacterium Streptomyces hygroscopicus in the Easter Island [194,195].
Molecules 27 08088 i013
Pitholide B (87), pitholide D (88), and pitholide E (89) were isolated and identified in P. microspora and Pithomyces sp. [67,196]. However, Pitholide E (89) did not exhibit any significant antifungal activity against Cladosporium cladosporioides, while Pitholide B (87) and Pitholide D (88) were not analyzed for their bioactivity [67]. In addition, Pitholides A (90) and C (91) were isolated from Pithomyces sp. derived from the marine tunicate Oxycorynia fascicularis, and their bioactivities were also not evaluated [196].
Molecules 27 08088 i014
P. microspora SC3082 was derived from the tropical tree Scaevola taccada, and a few new compounds (92–97) were isolated and characterized in the strain, including microsporaline A-D (92–95) [66]. Microsporalines B and C (93, 94) and gamahorin (96) displayed moderate antifungal activities against C. albicans (ATCC 10321) with MIC values of 25.0, 25.0, and 12.5 μg/mL, respectively, while microsporaline A and D (92, 95) and 8-acetoxy pestalopyrone (97) did not show bioactivities against C. albicans (ATCC 10321) with MIC values of > 100 μg/mL.
Molecules 27 08088 i015
Yang XL et al. [21] introduced ambuic acid and several of its derivatives, and more compounds have been discovered since then. For example, three new ambuic acid derivatives (98–100) were isolated and characterized in P. microspora found from the leaves of Corylus chinensis [122]. Among them, microsporol A (98) and microsporol C (100) exhibited moderately inhibitory effects on human 5-lipoxygenase (5-LOX), by 48.32% and 58.72%, respectively.
Molecules 27 08088 i016

3.11. Pestalotiopsis neglecta

Four new ambuic acid derivatives (101–104) were isolated from the solid culture of P. neglecta [123]. In the nitric oxide (NO) inhibition assay, the derivative 104 exhibited weak inhibitory activity against the NO production in the lipopolysaccharide (LPS)-induced macrophage with an IC50 value of 88.66 μM. Since NO shows a strong physiological function in plants and humans, the derivative 104 could explore the novel NO functions.
Molecules 27 08088 i017
Pestalotiochromenoic acids A-D (105–108), as well as two novel chromone derivatives, pestalotiochromones A (109) and B (110), were discovered for the first time in the marine algae-derived fungus P. neglecta SCSIO41403 [125]. All of these compounds (105–110) were inactive or showed weak cytotoxicity against seven human cancer cell lines, i.e., three renal cancer cell lines (ACHN, OS-RC-2, 786-O), three leukemia cell lines (HL-60, K-562, MOLT-4), and a liver hepatocellular carcinoma cell line (HepG2) (IC50 > 50 μM); however, these compounds showed obvious liver X receptors (LXRs) modulatory activities in a dose-dependent manner. From the liquid cultures of P. neglecta SCSIO41403, three new carboxylic acid derivatives, pestallic acids F (111) and G (112), pestalotiopyrone N (113), and a new diphenylketone derivative, neopestalone (114), were obtained [27]. In addition, other known compounds were found in the strain, including sesquicaranoic acid B (115) and monocycloalternarene B (116), which were not included in the articles by Yang XL et al. [21] and Xu J et al. [10]. However, these compounds (111–116) did not exhibit biological activities against Dengue virus virulence with 10 μM, while neopestalone (114) exhibited obvious COX-2 inhibitory activities, with the IC50 value of 5.8 μM.
Molecules 27 08088 i018

3.12. Pestalotiopsis palmarum

Four diphenyl ether derivatives, sinopestalotiollides A-D (117–120), and one natural α-pyrone product (121), were newly obtained from the ethyl acetate extract of the endophytic fungus P. palmarump isolated from the leaves of medicinal plant Sinomenium acutum in China [64]. Sinopestalotiollides A-C (117–119) and 5,6-dihydro-4-methoxy-6-hydroxymethyl-2H-pyran-2-one (121) exhibited moderate cytotoxicities against two human tumor cell lines, HeLa and HCT116, and showed weak cytotoxicities against human tumor cell line A549. IC50 values of sinopestalotiollide A (117) against HeLa, HCT116, and A549 were 18.92, 15.69, and 31.29 μM, respectively; IC50 values of sinopestalotiollide B (118) against the cell lines were 12.80, 22.67, and 44.89 μM, respectively; IC50 values of sinopestalotiollide C (119) were 14.66, 18.49, and 36.13 μM, respectively. IC50 values of 5,6-dihydro-4-methoxy-6-hydroxymethyl-2H-pyran-2-one (121) were 15.60, 24.35, and 47.82 μM, respectively.
Molecules 27 08088 i019

3.13. Pestalotiopsis sydowiana

** eggs of the sea urchin Strongylocentrotus intermedius (MIC50 = 40 µg/mL) [202].
Molecules 27 08088 i027
Five new ambuic acid derivatives (172–176) were found from an endolichenic fungus Pestalotiopsis sp. [142]. The suggested biosynthetic pathways of ambuic acid and its derivatives are shown in Figure 5.
Molecules 27 08088 i028
The bioactivities of these ambuic acid derivatives (172–176) were evaluated, and the results showed these compounds (172–176) did not exhibit significant cytotoxicity against several tumor cells, including A549, HepG 2, and HeLa cell lines (IC50 > 40 μM), nor did they show antibacterial activities against S. aureus, B. subtilis, and B. subtilis (MIC > 64 μg/mL) [142]. The antifungal assay showed that compounds 172 and 176 exhibited significant biological effects against Fusarium oxysporum with a MIC value of 8 μg/mL. In contrast, compound 176 potently inhibited Fusarium gramineum at 8 μg/mL, compared with the positive control ketoconazole (MIC value of 8 μg/mL). These compounds (172–176) did not exhibit bioactivities against B. cinerea, Alternaria solani, and Rhizoctonia solani (>64 μg/mL).
Molecules 27 08088 i029
From the fresh stem bark of Melia azedarach, an endophytic fungus, Pestalotiopsis sp., was isolated, and eight new caryophyllene sesquiterpenoids named pestaloporinates A-G (177–183) and 14-acetylhumulane (184) were identified from the solid cultures of the fungal strain [143]. These isolated compounds (177–184) were used to test for their inhibitory effects on nitric oxide production induced by lipopolysaccharide in the murine macrophage RAW 264.7 cell line. The results showed that pestaloporinate B (178) exhibited a potent inhibitory effect with an IC50 value of 19.0 μM, compared to the positive control (IC50 = 40.5 μM), while other compounds were inactive under 50 μM [143].
Molecules 27 08088 i030
The endophytic fungus Pestalotiopsis sp. was obtained from the leaves of Photinia frasery in China. Five new isocoumarin derivatives, pestalactone A–C (185–187) and pestapyrone D–E (188–189), together with two known compounds (190–191), were isolated from the solid cultures of the fungal strain [144]. Their bioactivity assay showed that only pestalactone C (187) exhibited potent antifungal activity against Candida glabrata (ATCC 90030) with a MIC50 value of 3.49 μg/mL. They were inactive against Gram-positive bacteria (S. aureus ATCC 25923 and B. subtilis ATCC 6633) and Gram-negative bacteria (B. subtilis ATCC 25922 and P. aeruginosa ATCC 9027) [144].
Molecules 27 08088 i031
A Pestalotiopsis sp. strain was found from a soft coral, and a pair of new enantiomeric alkaloid dimers, (−)- and (+)-pestaloxazine A (192–193), were isolated from the fungal strain [147]. (±)- pestaloxazine A, (−)-pestaloxazine A (192), and (+)-pestaloxazine A (193) showed different antiviral activity against EV71 (enterovirus 71) with IC50 values of 16.0, 69.1, and 14.2 μM, respectively. Their selectivity indices (SI) of anti-EV71 activity were 7.9, 2.1, and 9.2, respectively. They did not exhibit any bioactivity against the respiratory syncytial virus (RSV), coxsackie B3 virus (Cox-B 3), and H1N1 virus [147].
Molecules 27 08088 i032
Five alkenyl phenol and benzaldehyde derivatives, pestalols A-E (194–198), were isolated from the endophytic fungus Pestalotiopsis sp. AcBC2 deriving from the Chinese mangrove plant Aegiceras corniculatum (Myrsinaceae family) [151]. Bioactivity assay of the five compounds showed that (1) pestalol B (195) and pestalol C (196) exhibited antiproliferative effects at a range of 23.4–42.5 μM against 10 human tumor cell lines, including MCF-7, BT474, A549, DU145, H1975, SK-BR-3, K562, MOLT-4, U937, and BGC823; (2) pestalol A-D (194–197) showed significant effects on the influenza viruses H3N2 and H1N1 with IC50 values of 18.9–48.0 μM [151].
Molecules 27 08088 i033
Four novel polyketides, pestalpolyols A-D (199–202), were also isolated from solid fermentation products of Pestalotiopsis sp. cr013 [153]. The skeleton of 202 was almost the same as compound 201, except for one more carbon in a CH3CH2C = O group. These four compounds (199–202) did not exhibit any anti-fungal activities against Gaeumannomyces graminis, Fusarium moniliforme, Verticillium cinnabarium, and Phyricularia oryzae, nor any anti-bacterial activity against Pseudomonas solanacearum, S. aureus, and Salmonella typhimurium at 100 µg/disk. Neither of them (199–202) showed any nematicidal activities against Panagrellus redivivus and Caenorhabditis elegans [153]. Pestalpolyol A (199) possessed cytotoxicity against tumor cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480, with IC50 values of 10.4, 11.3, 2.3, 13.7, and 12.4 µM, respectively. Pestalpolyol B (200) showed an IC50 value of 10.6 µM against A-549, and Pestalpolyol D (202) exhibited IC50 values of 15.7 µM (HL-60), 31.2 µM (SMMC-7721), 10.7 µM (A-549), 23.7 µM (MCF-7), and 21.4 µM (SW480), respectively [153].
Molecules 27 08088 i034
The fungal strain Pestalotiopsis sp. cr014 is a mycoparasite of Cronartium ribicola, white pine blister rust of Pinus armandii in Sichuan Province, China. Nine new polyketides, pestalotic acids A-I (203–211), were isolated from solid fermentation products of Pestalotiopsis sp. cr014 [154]. In addition, pestalotic acid B (204), pestalotic acid C (205), pestalotic acid G (209), and pestalotic acid H (210) possessed antibacterial activities with MIC values of 0.78–12.5 µg/mL against Ralstonia solanacearum and Salmonella typhi [154].
Molecules 27 08088 i035
Pestalotiopsis sp. PG52 is a mycoparasite isolated from aeciospore piles of Aecidium pourthiaea, and four novel polyketides, pestalpolyols E–H (212–215), were isolated from solid fermentations of this fungal strain [155]. Bioactivity assays showed pestalpolyol F (213) possessed cytotoxicity against lung adenocarcinoma cell line A-549 with an IC50 value of 11.45 µM; pestalpolyol (214) exhibited weak cytotoxicity against four cell lines with IC50 values of 14.60 µM (leukemia cell line HL-60), 27.46 µM (hepatocarcinoma cell line SMMC-7721), 11.83 µM (A-549), and 18.50 µM (breast cancer cell line MCF-7); and pestalpolyol (215) showed cytotoxicity against three cell line with IC50 values of 22.85 µM (HL-60), 8.05 µM (A-549), and 38.89 µM (MCF-7) [155].
The endophytic fungus Pestalotiopsis sp. EJC07 was isolated from Bauhinia guianensis, a topical plant of the Amazon. Eight compounds, (4S)-4,8-dihydroxy-1-tetralone (216), uracil, uridine, p-hydroxybenzoic acid, ergosterol, ergosterol peroxide, cerevisterol, and ducitol, were isolated from the fungal strain, with (4S)-4,8-dihydroxy-1-tetralone (216), which was first reported in the Pestalotiopsis genus [203]. This study reported no assay on the bioactivity of (4S)-4,8-dihydroxy-1-tetralone (216).
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From the cultured broth of Pestalotiopsis sp. FT172, five ambuic acid derivatives, pestallic acids A–E (217–221), and (+)-ambuic acid (222), were isolated and identified [156]. All the compounds (217–222) were tested against human cancer cell lines, cisplatin sensitive, and resistant human ovarian carcinoma (A2780S and A2780cisR). Pestallic acid E (221) showed potential cytotoxicity with IC50 values of 3.3 and 5.1 μM for A2780S and A2780cisR, respectively; and (+)-ambuic acid (222) also exhibited inhibition on the two cancer cell lines with IC50 values of 10.1 and 17.0 μM, respectively [156].
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Cuautepestalorin (226) and its putative biosynthetic precursors, cytosporin M (223), cytosporin N (224), and oxopestalochromane (225), were isolated from the bioactive extract of Pestalotiopsis sp. [159]. The bioactivity assay showed that oxopestalochromane (225) and cuautepestalorin (226) showed modest inhibitory activities against α-glucosidase from S. cerevisiae, with IC50 values of 263.0 and 42.4 μM, respectively, 2 and 14 times more potent than acarbose (604.4 μM), which was used as the positive control [159].
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From the solid cultures of the endophytic fungus Pestalotiopsis sp. M-23, three new drimane sesquiterpenoids (227–229), the known 2α-hydroxyisodrimeninol (230), and a new isochromone derivative (231) were isolated and identified. The bioactivity assay showed that 11-dehydro-3a-hydroxyisodrimeninol (229) exhibited a weak inhibitory effect on B. subtilis with an IC50 value of 280.27 μM and that none of these compounds (227–231) showed obvious biological activity against S. aureus and M. luteus. However, drimane sesquiterpenoids were found in other fungi, animals, and plants and showed extensive bioactivities, such as antioxidant, anti-inflammatory, antibacterial, and antifungal [204,205,206,207,208,209,210,211]. Thus, drimane sesquiterpenoids from Pestalotiopsis species should be investigated in detail for their bioactivities.
Pestalotiopsis sp. Z233 was isolated from the algae Sargassum horneri, and two new sesquiterpenes, 1β,5α,6α,14-tetraacetoxy-9α-benzoyloxy-7βH-eudesman-2β,11-diol (232) and 4α,5α-diacetoxy-9α-benzoyloxy-7βH-eudesman-1β,2β,11,14-tetraol (233), were isolated from the cultured mycelia of the fungal strain under heavy metal stress (CuCl2) [162]. 1β,5α,6α,14-tetraacetoxy-9α-benzoyloxy-7βH-eudesman-2β,11-diol (232) and 4α,5α-diaacetoxy-9α-benzoyloxy-7βH-eudesman-1β,2β,11,14-tetraol (233) showed tyrosinase inhibitory activities with IC50 values of 14.8 µM and 22.3 µM (the standard tyrosinase inhibitor kojic acid with IC50 = 21.2 µM), respectively.
Molecules 27 08088 i039
Cytosporones were not introduced by Yang XL et al. [21] and Xu J et al. [10]. The endophytic fungus Pestalotiopsis sp. was isolated from the leaves of the Chinese mangrove R. mucronata, and 11 compounds were isolated, including six cytosporones (234–239) [146,150]. When these compounds (234–239) were tested at an initial concentration of 10 µg/mL, none of the compounds showed any significant biological activity against three cancer cell lines, L5178 Y, HeLa, and PC12 [146]. Thus, their bioactivities against bacteria and fungi should be tested.
Endophytic Pestalotiopsis sp. BC55 produces exopolysaccharide (EPS), with a maximum EPS value of 4.320 g/L in a 250 ml Erlenmeyer flask containing 75 mL potato dextrose broth supplemented with 7.66 g%/L glucose, 0.29 g%/L urea, and 0.05 g%/L CaCl2 with medium pH 6.93, after 3.76 days of incubation at 24 °C [152]. The EPS is a homopolysaccharide of (1 → 3)-linked-d-glucose. EPSs are also produced by other fungi and bacteria, such as F. solani [212], F. oxysporum [213], Stemphylium sp. [214], the mangrove endophytic fungus Aspergillus sp. Y16 [215], lactic acid bacteria [216,217], Bacillus mycoides [218], and Bacillus licheniformis [219]. EPS bioactivity greatly varied due to chain length, molecular weight, branching, etc. A bioactive EPS with Mw ~1.87 × 105 Da was isolated from endophytic fungus F. solani SD5 [212]. The isolated EPS showed in vitro anti-inflammatory and anti-allergic activity, and the EPS (1000 μg/mL) protects 55% of erythrocytes from hypotonic solution-induced membrane lysis. EPS produced by B. mycoides exhibited an anti-tumor effect [218]. EPS produced by B. mycoides showed low cytotoxicity against normal cells of baby hamster kidney (BHK) with an IC50 value of 254 μg/mL, while it exhibited an inhibitory effect against cancer cells of human hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma cells (Caco-2) with IC50 of 138 μg/mL and 159 μg/mL, respectively. Ren Q et al. [220] purified EPSs with a molecular weight of 2.7 × 106 Da to 1.7 × 107 Da from Lactobacillus casei and found that EPSs promote the differentiation of CD4 T lymphocytes into T-helper 17 cells in BALB/c mouse Peyer’s patches in vivo and in vitro. Thus, it is reasonable to speculate that EPSs produced by Pestalotiopsis species might exhibit various similar bioactivities.

4. Accurate Biosynthesis Pathways and Enhanced Accumulation of Secondary Metabolites in Pestalotiopsis

Nutritional and environmental factors greatly promote secondary metabolite biosynthesis in Pestalotiopsis species [80,83,85]. Under the best nutritional and environmental conditions, how to maximize the yield of secondary metabolites in Pestalotiopsis species is a key problem. Genetic modification in biosynthesis pathways of important secondary metabolites is the best choice with certainty. The aim of genetic modification is to increase or inhibit the activities of key enzymes in biosynthesis pathways of wanted secondary metabolites in order to increase their yield. Some key enzymes in the biosynthesis of secondary metabolites in Pestalotiopsis species have been identified to date, improving our knowledge about accurate biosynthesis pathways and enhancing the accumulation of novel secondary metabolites.

4.1. Transcription Factors Involved in Secondary Metabolite Biosynthesis in Pestalotiopsis

Given the roles of transcription factors in gene expression, transcription factors involved in the biosynthesis of secondary metabolites in Pestalotiopsis species have been widely studied. Two transcription factors, PfmaF and PfmaH, cooperatively regulate 1,8-dihydroxy naphthalene (DHN) melanin biosynthesis in P. fici. PfmaH, as a pathway-specific regulator, mainly regulates melanin biosynthesis, and PfmaF functions as a broad regulator to stimulate PfmaH expression in melanin production [90]. In addition, PfmaH directly regulates the expression of scytalone dehydratase, which catalyzes the transition of scytalone to 1,3,8-trihydroxynaphthalene (T3HN), which is reduced to vermelone, and vermelone is converted into DHN. Zhang P et al. [90] disrupted the gene PfmaF using the CRISPR/Cas9 system. They found that the disruption affected neither DHN melanin distribution nor conidia cell wall integrity in P. fici. Yet, the overexpression of PfmaF leads to heavy pigment accumulation in P. fici hyphae. Recently, two new transcription factors, Pmr1 and Pmr2, were identified in P. micropspora [221]. Pmr1 and Pmr2 were located in the gene cluster for melanin biosynthesis and both of them regulated the expression of genes in the melanin biosynthesis cluster. In Δpmr1 and Δpmr2 mutant strains, most genes in the gene cluster (including 21 genes, i.e., GEM11355_g–GEM11375_g) were significantly upregulated. Their upregulation is related to increased yield of secondary metabolites in the mutant strains Δpmr1, compared with the wild type (WT). Meanwhile, HPLC analysis showed that the pestalotiollide B peak at 3.3 min was much greater in the Δpmr1 and Δpmr2 strains than that in WT; moreover, this increment in Δpmr1 was significantly greater than that in Δpmr2. In addition, Pmr1 played a larger regulatory role in secondary metabolism than Pmr2.
PfZipA, on the other hand, is one of the bZIP transcription factors in P. fici. Without oxidative treatment, the ΔPfzipA mutant strain of P. fici produced less isosulochrin and ficipyrone A than wild type [78]. However, PfZipA mediates the sensitivity of P. fici to oxidative stress caused by the oxidative reagents that-butyl hydroperoxide (tBOOH), diamide, H2O2, and menadione sodium bisulfite (MSB). tBOOH treatment decreased the production of iso-A82775C and pestaloficiol M in ΔPfzipA strain; MSB treatment decreased the production of RES1214-1 and iso-A82775C; however, it increased pestaloficiol M production in the mutant; and H2O2 treatment resulted in enhanced production of isosulochrin, RES1214-1, and pestheic acid (23), yet decreased ficipyrone A and pestaloficiol M in ΔPfzipA strain, compared to the wild type [78].

4.2. Histone Acetylation

Histone acetylation is an important modification of histone proteins, which plays an important role in condensing and relaxing DNA. Histone acetylation is also involved in the biosynthesis of secondary metabolites in Pestalotiopsis species. Zhang Q et al. [113] identified a B-type histone acetyltransferase, Hat1, in the P. microspora. Secondary metabolites dramatically decreased in a hat1 deletion mutant strain, suggesting HAT1 functions as a regulator of secondary metabolism. Therefore, it is reasonable to speculate that the overexpression of the gene hat1 improves the biosynthesis of secondary metabolites in the fungus, thus, its overexpression mutant strains might be used for specific metabolites. In P. microspora, an MYST histone acetyltransferase encoded by the gene MST2 modulates secondary metabolism and conidial development [222]. Deleting the gene (mst2) caused serious growth retardation and impaired conidial development, e.g., delayed and reduced conidiation and aberrant conidia capacity. At the same time, overexpression of mst2 triggered earlier conidiation and higher conidial production. Deletion of mst2 also reduced the production of secondary metabolites in P. microspora [222]. In P. microspora NK17, Niu X et al. [112] found that a putative histone deacetylase gene (HID1) played an important role in the biosynthesis of pestalotiollide B. In the hid1 null mutant, the yield of pestalotiollide B increased approximately 2-fold to 15.90 mg/L. In contrast, the deletion of gene hid1 resulted in a dramatic decrease in conidia production of P. microspora NK17. These results suggest that the histone deacetylase HID1 is a regulator, concerting secondary metabolism and development, such as conidiation, in P. microspora.

4.3. Polyketide Synthases

Polyketides possess diverse chemical structures and biological activities and are the most important sources of novel secondary metabolites in plants, bacteria, and fungi. Polyketide synthases (PKSs) catalyze the biosynthesis of polyketides. While type I and type II PKSs exist as large protein complexes, type III PKSs are relatively small homodimeric proteins (~45 kDa monomer). In Pestalotiopsis species, PKSs are involved in the biosynthesis of some secondary metabolites. For example, the biosynthesis of pestalotiollide B is controlled by polyketide synthase [111]. Chen L and co-workers successfully deleted 41 out of 48 putative PKSs in the genome of P. microspora NK17. Furthermore, they found that 9 of the 41 PKS deleted strains significantly increased the biosynthesis of pestalotiollide B, and the deletion of pks35 increased pestalotiollide B by 887% [111].
The fungal products dibenzodioxocinones promise a novel class of inhibitors against cholesterol ester transfer protein [112]. A gene cluster of 21 genes, including PKS8 encoding a polyketide synthase, was defined, and disruption of genes in the cluster led to the biosynthesis of loss of dibenzodioxocinones [120]. Of the 21 genes, 5 genes, i.e., GME11356, GME11357, GME11358, GME11365, and GME11367, were deduced to participate in the generation of the backbone structure, and three regulatory genes, i.e., GME11360, GME11369, and GME11370, were also identified.
After forming polyketides, they can be converted into other secondary metabolites. The pestheic acid biosynthetic gene (pta) cluster was identified through genome scanning of the fungus P. fici. The biosynthetic pathway was elucidated through gene disruption intermediate detection and enzymatic analysis [82]. The results showed that the pestheic acid biosynthesis proceeded through the formation of the polyketide backbone, cyclization of a polyketo acid to a benzophenone, chlorination, and construction of the diphenyl ether skeleton through oxidation and hydrolyzation. The gene PTAA is important in pestheic acid biosynthesis in P. fici. Pestheic acid was abolished in the ptaA disruption mutants of P. fici [82]. In the pestheic acid biosynthesis pathway, the gene PTAM encodes a flavin-dependent halogenase, catalyzing chlorination. Inactivation of flavin-dependent halogenase from the Chaetomium chiversii radicicol locus yielded dechloro-radicicol (monocillin I) [223]. Thus, in P. fici, PTAM (ptaM) disruption might result in a change in pestheic acid biosynthesis.

4.4. Other Regulatory Proteins and Enzymes

The Snf1/AMPK is highly conserved in the eukaryotes and acts as a central regulator of carbon metabolism and energy production. In the filamentous fungus P. microspora, SNF1 concerts carbon metabolism and filamentous growth, conidiation, cell wall integrity, stress tolerance, and the biosynthesis of secondary metabolites [224]. The Snf1 deletion strain of P. microspora NK17 (∆snf1) displayed remarkable retardation in vegetative growth and pigmentation. Furthermore, it produced a diminished number of conidia, even in the presence of glucose, and Snf1 deletion caused damage to the cell wall of P. microspora [224]. In addition, Pestalotiollide B was considerably reduced in the mutant strain ∆snf1. These results demonstrate that SNF1 is a regulator of secondary metabolism and may be involved in either the activation or silencing of certain gene clusters in P. microspora NK17. Therefore, the more accurate function of SNF1 should be elucidated in secondary metabolite biosynthesis research.
Evidence shows biosynthesis of secondary metabolites and development are correlated processes in fungi, and pleiotropic proteins regulate the equilibrium between the biosynthesis of secondary metabolites and development. A global regulator, RsdA (regulation of secondary metabolism and development), was identified through genome-wide analysis and deletion of the regulator gene in the endophytic fungus P. fici [225]. Deleting rsdA significantly reduced asexual development, resulting in low sporulation, abnormal conidia, and major secondary metabolites (such as asperpentyn, fificiolide A, and chloroisosulochrin) while remarkably increasing melanin pigment production. In addition, pestheic acid, a basic building block for a group of structurally diverse compounds, was completely abolished in the ΔrsdA strain, implying that the biosynthesis of pestheic acid analogs was dramatically reduced.
Canonical Gcn2/Cpc1 kinase is an amino acid sensor and regulates the expression of target genes in response to amino acid starvation. When the mutant strain Δgcn2 of P. microspora was cultured in the presence of 3AT (5 mM) to mimic amino acid starvation conditions, biosynthesis of pestalotiollide B was almost inhibited [114]. Meanwhile, the loss of gcn2 led to a less-pigmented phenotype of P. microspora [114]. All the results demonstrate that the protein encoded by gcn2 is a regulator of secondary metabolism and may be involved in either activation or silencing of gene clusters in P. microspora.
G-protein-mediated signaling pathways regulate fungal morphogenesis, development, pathogenesis, and secondary metabolism [226,227,228,229,230,231]. In Pestalotiopsis species, G protein-mediated signaling regulates secondary metabolites. The gene pgα1 putatively encodes the α-subunit of a group I G protein in P. microspora NK17. The pgα1 deletion mutants showed retarded vegetative growth, mycelium aging, premature conidiation, deformed conidia, significantly increased melanin production, and a sharp decrease in the production of pestalotiollide B [13]. Meanwhile, the expression of pks1, which encodes melanin polyketide synthase involved in 1,8-dihydroxy naphthalene (DHN) melanin biosynthesis, was upregulated 55-fold in pgα1 deletion mutants. All the results imply obvious changes in the biosynthesis of different secondary metabolites in pgα1 mutants. In addition, the deficiencies of pestalotiollide B production and conidiation in Δpgα1 mutants could not be rescued by deletion or overexpression of the gene hid1 encoding histone deacetylase, suggesting that the protein PGα1 can override the effect of hid1 on pestalotiollide B production and conidiation.
In the fungus P. microspora, two genes, choA and choC, encode two phospholipid methyltransferases. choC deletion mutants (choCΔ) resulted in defects in phosphatidylcholine production, vegetative growth, and development of asexual structure [49], suggesting that genetic modification might regulate secondary metabolite biosynthesis in Pestalotiopsis species. However, choA, but not choC, was required to produce pestalotiollide B [49], suggesting distinct roles of the two genes.
The earlier examples demonstrate changes in the biosynthesis of secondary metabolites in Pestalotiopsis species by molecular tools, especially gene editing. Therefore, key genes encoding important enzymes in secondary metabolite biosynthesis in Pestalotiopsis species should be cloned, and the overexpression or deletion of these key genes is useful for enhanced biosynthesis of important secondary metabolites. More importantly, accurate biosynthesis pathways of secondary metabolites are the premise. Based on these basic studies on the effects of secondary metabolites in Pestalotiopsis species on human health, animals, and plants and the identification of their accurate biosynthesis pathways, it is possible to enhance biosynthesis and the accumulation of key secondary metabolites in the future. The industrial production of important secondary metabolites in this way will become possible.

5. Concluding Remarks and Future Perspectives

Given the important effects of secondary metabolites from Pestalotiopsis species on human health, animals, and plants, two aspects, i.e., the effects of these secondary metabolites and their accurate biosynthesis pathways, are vital. Therefore, more studies should focus on their accurate biosynthesis pathways to enhance biosynthesis and accumulation, further establishing the foundation for the industrial production of secondary metabolites from Pestalotiopsis species. Gene editing is a valuable method for fully comprehending secondary metabolite biosynthesis processes; however, it is very difficult to establish gene-editing systems for some Pestalotiopsis species, despite genome editing systems having been established for few Pestalotiopsis species, such as P. fici and P. microspora [90,232,233,234]. Furthermore, more effective gene-editing tools are to be developed and, therefore, long-term efforts are in the pipeline.
In addition, improvements for the best growth conditions are useful for enhanced biosynthesis and accumulation of secondary metabolites. For example, the addition of some chemicals in the culture medium promotes the biosynthesis of secondary metabolites, such as salicylic acid [235]. Meanwhile, the co-cultivation of fungi and bacteria can also trigger the biosynthesis of secondary metabolites. For example, the co-cultivation of Aspergillus flavipes and B. subtilis triggers the biosynthesis machinery of taxol [236]. At present, are isa no reports on the co-cultivation of Pestalotiopsis species with other microbes. Many gene clusters for the biosynthesis of secondary metabolites in filamentous fungi often stay silent under some culture conditions because of the absence of interaction with bacteria. For instance, Brakhage and colleagues have discovered that the silent secondary metabolite gene cluster for orsellinic acid (ors) in the filamentous fungus Aspergillus nidulans is activated upon physical interaction with the bacterium Streptomyces rapamycinicus, and the interaction of the fungus with this distinct bacterium led to increased acetylation of histone H3 lysines 9 and 14 at the ors gene cluster, thus to its activation [237,238,239]. Then, they identified the Myb-like transcription factor BasR, a master regulator of bacteria-triggered production of fungal secondary metabolites, by chromatin map** [240]. However, the interaction between Pestalotiopsis species and bacteria and key regulator nodes for transduction of the bacterial signals in the fungi is unclear. Certainly, activating silent gene clusters in Pestalotiopsis species is a good strategy for enhanced biosynthesis and accumulation of fungal secondary metabolites, just as in the Brakhage and Schroeckh advocated strategies [241]. Furthermore, as mentioned above, gene editing is a good and useful approach to increase the yield of secondary metabolites. We should try our utmost to establish whole feasible systems of gene editing for important Pestalotiopsis species. At present, the Pestalotiopsis species investigated are only a small part of this genus, and more species are yet to be studied and developed for human health.

Author Contributions

C.W. planned and wrote most parts of the article. Y.Y. collected some literature and then revised the article. Y.W. re-illustrated all the chemical structures of these compounds in the article. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (grant number: 31870378).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Necla Pehlivan (Recep Tayyip Erdogan University, Rize 53100, Turkey) for reviewing and revising the rough manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 27 08088 g001 550
Figure 1. Synthesis pathway of disseminins and spiciferones.
Figure 1. Synthesis pathway of disseminins and spiciferones.
Molecules 27 08088 g001
Molecules 27 08088 g002 550
Figure 2. Conversion of 1-undecene-2,3-dicarboxylic acid and maldoxin to chlorotheolides via Diels-Alder reactions [170].
Figure 2. Conversion of 1-undecene-2,3-dicarboxylic acid and maldoxin to chlorotheolides via Diels-Alder reactions [170].
Molecules 27 08088 g002
Molecules 27 08088 g003 550
Figure 3. The hypothetical biosynthetic pathways for chlorotheolides [170].
Figure 3. The hypothetical biosynthetic pathways for chlorotheolides [170].
Molecules 27 08088 g003
Molecules 27 08088 g004 550
Figure 4. Plausible biogenetic correlation of pestauvicomorpholine A and three alternariol analogues [175].
Figure 4. Plausible biogenetic correlation of pestauvicomorpholine A and three alternariol analogues [175].
Molecules 27 08088 g004
Molecules 27 08088 g005 550
Figure 5. The suggested biosynthetic pathways of ambuic acid and its derivatives [142].
Figure 5. The suggested biosynthetic pathways of ambuic acid and its derivatives [142].
Molecules 27 08088 g005
Table
Table 1. Identified metabolites from Pestalotiopsis species and their bioactivities.
Table 1. Identified metabolites from Pestalotiopsis species and their bioactivities.
Fungal SpeciesMetabolitesBioactivityReferences
P. adustapestalachlorides A–Cantifungal[69]
diterpenoid [70]
P. besseyifuranones [71]
P. brevisetataxolanticancer[16,17]
P. crassiusculaa new coumarin and six known compounds [72]
P. diploclisiapestalotioquinols G and H, pestalotioquinol A, phomonitroester, (R)-4,6,8-trihydroxy-3,4-dihydronaphthalen-1(2H)-one, and scylatoneantimalarial and cytotoxic activity[73]
P. disseminata6-hydroxypunctaporonin E, 6-hydroxypunctaporonin B, and 6-hydroxypunctaporonin Aanti-bacteria[74]
disseminins A–E, spiciferones D and E [75]
P. ficichloropupukeananin and chloropestolidesantimicrobial, antitumor, and anti-HIV activities[76]
pestaloficiols A–Einhibitory effects on HIV-1 replication[77]
isosulochrin, ficipyrone A, pestheic acid, iso-A82775C, pestaloficiol M, RES1214-1, and iso-A82775C [78]
pestalofones A–E, isosulochrin, isosulochrin dehydrate, and iso-A82775Cinhibitory effects on HIV-1 replication and antifungal activity[79]
chloropestolide Aantitumor[80]
chloropupukeanolides C–Ecytotoxicity[81]
pestheic acid [82]
chloropupukeananin [83]
melanin [84]
chloropupukeanolides A and B, chloropupukeanone Aanti-HIV-1 and cytotoxic activity[85]
isoprenylated chromone derivatives [86]
Chloropestolides B–G [87]
pestaloficins A–E [88]
pestaloficiols Q–S [89]
DHN melanin [90]
2H-pyran-2-one and 2H-furan-2-one derivatives [91]
P. flavidulaspiroketal derivativescytotoxicity[92]
P. foedanpestafolide A, pestaphthalide A and Bantifungal activity[93]
(−)-(4S, 8S)-foedanolide and (+)-(4R, 8R)-foedanolide [94]
monoterpene derivativesantifungal[95]
P. guepiniimetabolites of ciprofloxacin and norfloxacin [96]
culture broth extractinhibit actinomycete growth[97]
pestheic acid or dihidromaldoxingenotoxicity and mutagenicity[98]
alpha-pyrones [99]
P. hainanensistaxol [19]
caryophyllene-Type Sesquiterpenes [100]
P. heterocorni7-hydroxy-5-methoxy-4,6-dimethyl-7-O-α-L-rhamnosyl-phthalide and 7-hydroxy-5-methoxy-4,6-dimethyl-7-O-β-D-glucopyranosyl-phthalide [101]
heterocornols A–L, methyl-(2-formyl-3-hydroxyphenyl) propanoate, cladoacetal A, xylarinol A, agropyrenol, vaccinol G, (R)-3-hydroxy-1-[(R)-4-hydroxy-1,3-dihydroisobenzofuran-1-yl]butan-2-one, and (R)-3-hydroxy-1-[(S)-4-hydroxy-1,3-dihydroisobenzo -furan-1-yl]butan-2-onecytotoxicity and antifungal[29]
pestaloisocoumarins A and B, isopolisin B, pestalotiol A, gamahorin, pestalachloride B, pestalachloride E, pestalalactone atropisomers (8a/8b),cytotoxicity[30]
heterocornols M and N, heterocornols O and Panticancer[28]
P. humuspestynolantibacterial and antifungal activity, weak cytotoxicity[102]
pestiocandinantibacterial and antifungal activity[103]
P. jesterijesterone and hydroxy-jesteroneselective antimycotic activity[104]
P. karsteniipestalrone A, pestalrone B, pestalotin, hydroxypestalotincytotoxic activity, antiprotozoal activity[42]
P. leucothësBS, GS, and YSImmunomodulatory[105]
immunomodulatory effects[106]
P. mangiferae4-(2,4,7-trioxa-bicyclo [4.1.0] heptane-3-yl) phenolantibacterial and antifungal activity[107]
P. microsporataxolantiproliferative activity[11,108]
ɑ-pyrone [109]
(+)-dendocarbin L, (+)-sydonic acid, and (+)-sydowic acidcytotoxicity[68]
isopestacinantifungal and antioxidant activities[110]
pestalotiollide B [49,111,112,113]
pestalotiollide B, melanin [114]
7-epi-10-deacetyltaxolinduces apoptosis[115]
taxol, pestalotiollide B, 1, 8-dihydroxy naphthalene melaninantitumor[13]
melanin [116]
ursolic acid [117]
pestalotioprolides C, D–H, 7-O-methylnigrosporolide, pestalotioprolide B, seiricuprolide, nigrosporolide, and 4,7-dihydroxy-13-tetradeca-2,5,8-trienolidecytotoxic[118]
dibenzodioxocinonsinhibitors of cholesterol ester transfer protein[119,120]
pestalotioquinols A and Bneuroprotective[121]
pitholide E, pitholide B, pitholide D, pestalotin, PC-2, tyrosol, 4-oxo-4H-pyran-3-acetic acid [67]
2H-pyranone and isocoumarin derivativesantifungal[66]
Microsporols A–C, ambuic acid5-lipoxygenase (5-LOX) inhibitory effects[122]
P. neglectaambuic acid derivativesinhibitory activity against the NO production[123]
crude methanol and ethyl acetate extractantibacterial activity[124]
pestalotiochromenoic acids A–D, pestalotiochromones A and Bliver X receptors modulators[125]
ambuic acidanti-inflammatory action[126]
benzophenonesinhibit pancreatic cancer cells[31]
Ene-yne Hydroquinones [26]
pestalopyrones A–D [127]
pestallic acids F and G, pestalotiopyrone N, neopestalone, sesquicaranoic acid B, monocycloalternarene B, pestalone, 2,4-dihydroxy-3,5,6-trimethyl benzoic acid, and citreorosein [27]
P. palmarumpsinopestalotiollides A–D, 3′-O-methyldehydroisopenicillide, ∆1′3′-1′-dehydroxypenicillide, dehydroisopenicillide, 2′-hydroxy-3′,4′-didehydropenicillide, scirpyrones A, 5,6-dihydro-4-methoxy-2H-pyran-2-one, LL-P880α, (6S,1′S,2′R)-LL-P880b, photipyrone B, PC-2, (1′S,2′R)-LL-P880γ, necpyrone Ccytotoxic[128]
P. paucisetataxolanticancer[15]
P. photiniaephthalide derivativesagainst plant pathogens[129]
photipyrones A, B, Cmodest inhibitory effects on the growth of MDA-MB-231[130]
4-(3′,3′-dimethylallyloxy)-5-methyl-6-methoxyphthalideinduced G1 cell cycle arrest and apoptosis in a dose-dependent manner[131]
4-(3′,3′-Dimethylallyloxy)-5-methyl-6-methoxy-phthalidecytotoxicity[132]
three new phthalide derivatives and six known phthalide derivativesantifungal activities[133]
photinides A–Fcytotoxic[52]
Pestalotiopsis sp.RES-1214-1 and -2non-peptidic endothelin type A receptor antagonists[134]
Pestalotiopsis sp.pestalotiopamide E [135]
Pestalotiopsis sp.pestalotiopens A and B [136]
Pestalotiopsis sp.pestalactams A–C [137]
Pestalotiopsis sp.pestaloficiol J, (±)-pestaloficiol X [138]
Pestalotiopsis sp.pestaloquinols A and B [139]
Pestalotiopsis sp.demethylincisterol A3, dankasterone B, (22E, 24R)-ergosta-7,9, 22-triene-3β, 5α, 6α-triol, ergosta-5,7,22-trien-3-ol, 5,8-epidioxy-5,8-ergosta-6,22E-dien-3-ol, stigmastan-3-one, stigmast-4-en-3-one, stigmast-4-en-6-ol-3-one, flufuran, (2-cis, 4-trans)-abscisic acid, similanpyrone B.induce G0/G1 cell cycle arrest and apoptosis in human cancer cells[140]
Pestalotiopsis sp.pestaloporonins [141]
Pestalotiopsis sp.polyketide-terpene hybrid metabolites [142]
Pestalotiopsis sp.pestaloporinates A–G and 14-acetylhumulane [143]
Pestalotiopsis sp.isocoumarin derivativesantifungal[144]
Pestalotiopsis sp. pestalotiopsolide A, taedolidol and 6-epitaedolidol [41]
Pestalotiopsis sp.(±)-pestalachloride Dantibacterial[145]
Pestalotiopsis sp.cytosporones J-N, pestalasins A-E, pestalotiopsoid A, cyclosporine C, dothiorelone B, and 3-hydroxymethyl-6,8-dimethoxycoumarin (13). [146]
Pestalotiopsis sp.(+)- and (−)-pestaloxazine Aantiviral[147]
Pestalotiopsis sp.pestalotiopsins A and Bimmunosuppressive[148]
Pestalotiopsis sp.ambuic acid and torreyanic acid derivativesantimicrobial activity[149]
Pestalotiopsis sp. pestalotiopsones A–Fmoderate cytotoxicity[150]
Pestalotiopsis sp. AcBC2pestalols A–E, 4-hydroxyphenethyl 2-(4-hydroxyphenyl) acetate, r-hydroxyphenyl acetic acid methyl ester, transharzialactones A and F, 3-hydroxy-3-methyl-d-lactone, 3β,5α, 9α-trihydroxy-7, 22-en-ergost-6-one, and 3b-hydroxy-sterolcytotoxicity, inhibitory activities against Influenza A virus subtype (H3N2), Swine Flu (H1N1) viruses, tuberculosis[151]
Pestalotiopsis sp. BC55exopolysaccharide [152]
Pestalotiopsis sp. cr013pestalpolyols A–Dcytotoxic[153]
Pestalotiopsis sp. cr014pestalotic acids A–Iantibacterial[154]
Pestalotiopsis sp. PG52pestalpolyols E–Hcytotoxic activities[155]
Pestalotiopsis sp. EJC07(4S)-4,8-dihydroxy-1-tetralone, uracil, uridine, p-hydroxybenzoic acid, ergosterol, ergosterol peroxide, cerevisterol and ducitol [74]
Pestalotiopsis sp. FT172pestallic acids A–Eanti-proliferative[156]
Pestalotiopsis sp. HC02pestalotines A and B [38]
Pestalotiopsis sp. HHL101pestalotiopisorin B [157]
Pestalotiopsis sp. HQD-6pestalotiopin B and pestalotiopyrone Nvery weak cytotoxic[158]
Pestalotiopsis sp. IQ-011cuautepestalorin, cytosporin M, cytosporin N, oxopestalochromane, pestaloneinhibitory properties against α-glucosidase from S. cerevisiae[159]
Pestalotiopsis sp. M-23drimane sesquiterpenoids, 2α-hydroxyisodrimeninol, a new isochromone derivativeweak antibacterial[160]
Pestalotiopsis sp. PSU-MA69pestalochromones A–C, pestalotethers A–D, pestaloxanthone, pestalolideantifungal activity against Candida albicans and Cryptococcus neoformans[161]
Pestalotiopsis sp. Z2331β,5α,6α,14-tetraacetoxy-9α-benzoyloxy-7β H-eudesman-2β,11-diol and 4α,5α-diacetoxy-9α-benzoyloxy-7βH-eudesman-1β,2β,11,14-tetraoltyrosinase inhibitory activities[162]
Pestalotiopsis spp.ambuic acidantifungal[163]
Pestalotiopsis spp.chromones, cytosporones, polyketides, terpenoids and coumarins [164]
P. sydowiana1-O-methyldehydroisopenicillide, pestalotiollide B, pestalotiollide A, dehydroisopenicillide, 6-hydroxymethyl-4-methoxy-5,6-dihydro-2H-pyran-2-one, pestalotiopyrone D, pestalotiopyrone E, pestalotiopyrone G, LL-P880b, and photipyrone B20S proteasome inhibitory activities[165]
cyclo(-Leu-Pro) and 4-hydroxyphenylacetamideantimicrobial,[33]
P. terminaliaetaxolanticancer[18]
P. theaechloroisosulochrin, ficipyrone A and pestheic acidstrong activity against respiratory syncytial virus[166]
pesthetoxin [167]
pestalotheols A–Dinhibitory effect on HIV-1 LAI replication[168]
pestalazines and pestalamidesinhibitory effects on HIV-1 replication and antifungal activity [169]
chlorotheolides A and B, 1-undecene-2,3-dicarboxylic acid, maldoxin [170]
pestalotiones A–D [171]
chloropupukeananin and pestalofone Cregulate autophagy through AMPK and Glycolytic Pathway[172]
pestathenols A and B, pestatheranone A, punctaporonins O, P, and R, ficifuranone B, and decarestrictine D [173]
pestalothenin A–Ccytotoxic and antibacterial activity[174]
P. uvicolapestauvicomorpholine A and three alternariol analoguescytotoxicity against mouse melanoma (B16-BL6) cell line[175]
bilobalidesuppresses adipogenesis in 3T3-L1 adipocytes via the AMPK signaling pathway; protect BV2 microglia cells against OGD/reoxygenation injury[176,177,178]
P. vacciniivaccinols J-S, trans-sordarial, trans-sordariol, cis-sordariol, 4-hydroxyphthalide, pestalotiopin A [32]
P. versicolor4,6-dihydroxy-7-formyl-3-methyl coumarin, 6-[(7S,8R)-8-propyloxiran-1-yl]-4-methoxy-pyran-2-onedevoid of significant antifungal activity against F. solani, Ustilago maydis, and C. albicans[179]
P. virgatulapestalospiranes A and B [180]
9-hydroxybenzo[C]oxepin-3[1H]-one [181]
virgatolides A–C [182]
P. yunnanensispestalotic acids A–Gsignificant antimicrobial activity[183]
P. zonatapestalrones A and B, pestalotin, hydroxypestalotin, pestazonatic acid, necpyrones A–B [184]
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Wu, C.; Wang, Y.; Yang, Y. Pestalotiopsis Diversity: Species, Dispositions, Secondary Metabolites, and Bioactivities. Molecules 2022, 27, 8088. https://doi.org/10.3390/molecules27228088

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Wu C, Wang Y, Yang Y. Pestalotiopsis Diversity: Species, Dispositions, Secondary Metabolites, and Bioactivities. Molecules. 2022; 27(22):8088. https://doi.org/10.3390/molecules27228088

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Wu, Chu, Yun Wang, and Yujie Yang. 2022. "Pestalotiopsis Diversity: Species, Dispositions, Secondary Metabolites, and Bioactivities" Molecules 27, no. 22: 8088. https://doi.org/10.3390/molecules27228088

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