Austin-Type Meroterpenoids from Fungi Reported in the Last Five Decades: A Review

Abstract

Austin was first isolated as a novel polyisoprenoid mycotoxin from Aspergillus ustus in 1976. Subsequently, some new austin-type meroterpenoids (ATMTs) have been continually found. This review attempts to give a comprehensive summary of progress on the isolation, chemical structural features, biological activities, and fungal biodiversity of 104 novel ATMTs from 5 genera of terrestrial- and marine-derived fungi reported from October 1976 to January 2023. The genera of Penicillium and Aspergillus are the two dominant producers, producing 63.5% and 30.8% of ATMTs, respectively. Moreover, about 26.9% of ATMTs display various pronounced bioactivities, including insecticidal, anti-inflammatory, cytotoxicity, antibacterial, and PTP1B inhibitory activities. The chemical diversity and potential activities of these novel fungal ATMTs are reviewed for a better understanding, and a relevant summary focusing on the source fungi and their taxonomy is provided to shed light on the future development and research of austin-type meroterpenoids.

1. Introduction

Microbial secondary metabolites differ from primary nutrients in that they are not essential for growth, but they play a vital role in the survival and adaptation of microbes in nature [1]. Fungi attract much attention from chemists and biologists due to the production of secondary metabolites with diverse structural skeletons and interesting bioactivities. Austin-type meroterpenoids (ATMTs) are a family of hybrid natural products with high diversity of intriguing scaffolds, but only 104 ATMTs have been characterized, which are a relatively rare branch of the terpenoid family and have often been isolated from fungi, especially from the genera Penicillium and Aspergillus [2,3,4,5,6,7,8]. The naturally occurring meroterpenoids derived from 3,5-dimethylorsellinic acid (DMOA) incorporated with farnesyl pyrophosphate (FPP) are the most common subclass [9,10,11,12,13], of which ATMTs are a class of special and important constituents. Based on the number of rings of the initial meroterpenoid in their biosynthesis pathway, ATMTs are classified into four categories, including tetracyclic, pentacyclic, hexacyclic, and heptacyclic systems. Interestingly, different types of ATMTs display broad and impressive biological activity [14,15,16], including insecticidal, antiphlogistic, antimicrobial, and antineoplastic effects, etc.

To date, no individual and comprehensive identification of the chemical structures of ATMTs has been reported. Therefore, this review was prepared to provide an overall coverage of the chemical constituents of the ATMTs reported in the last five decades (from October 1976 to January 2023) originating from fungi according to a classification of their chemical skeletons (two databases were used for the search: SciFinder and Web of Science). This review will provide information on the isolation, chemical structural features, biological activities, and fungal biodiversity of ATMTs, which will facilitate further research and exploitation of these structures. In this review, the biosynthesis pathways of these ATMTs are not discussed as they have been extensively reviewed by Wang, Abe, and Brakhage [17,18,19,20].

2. Austin-Type Meroterpenoids Compounds

2.1. Tetracyclic Systems Austin-Type Meroterpenoids

2.1.1. Tetracyclic Systems-Rings A and B Are Spirocyclic

This subgroup of ATMTs is characterized by a tetracyclic spirocyclic systems with six members (1–6) (Figure 1), including austinoneol (1) that was obtained from a Penicillium sp. [21] that was isolated from the root bark of Melia azedarach after surface sterilization and cultivated for three weeks on sterilized rice. The filamentous fungus Aspergillus nidulans has previously been found to produce two meroterpenoids, austinol and dehydroaustinol. The use of targeted deletions revealed that two separate gene clusters are required for meroterpenoid biosynthesis. One is a cluster of four genes including the polyketide synthase gene, ausA. The second is a cluster of 10 additional genes, including the prenyltransferase gene, ausN, located on a separate chromosome. Chemical analysis of mutant extracts enabled isolation of preaustinoid A5 (2), preaustinoid A4 (3), and preaustinoid A3 (4), which are either intermediates or shunt products from the biosynthetic pathway [17] (Figure 1). The filamentous fungus Aspergillus oryzae NSAR1 is used as part of a heterologous fungal expression system; Aspergillus oryzae NSAR1 is a quadruple auxotrophic mutant strain (niaD⁻, sC⁻, ΔargB, adeA⁻) that is used to produce austinoid C (5) [18]. Furthermore, one unusual austin-type meroterpenoid is penicianstinoid C (6), which was the first ATMT with a unique 6/6/6/5 rearranged tetracyclic skeleton possessing two unusual spirocyclic moieties (2-oxaspiro[5.5]undeca-4,7-dien-3-one and 6-methylene-2-oxaspiro[4.5]decane-1,4-dione); it was obtained from the mangrove-derived fungus Penicillium sp. TGM112. In addition, this compound shows inhibitory activity against newly hatched larvae of Helicoverpa armigera Hubner (IC₅₀ = 100 μg/mL) [22].

2.1.2. Tetracyclic Systems-Rings A and B Are Bicyclic Fused

An endophytic fungus Penicillium sp. is cultured from solid rice medium and was isolated from the root bark of Melia azedarach. It produced two new tetracyclic system ATMTs, preaustiniod A (7) and B (11), and they exhibited moderate bacteriostatic effects on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus sp. [23] (Figure 2). Genome mining of the fungus Aspergillus oryzae NSAR1 led to the isolation of three tetracyclic system ATMTs, preaustinoid C (8), 5-hydroxyberkeleyone A (16), and berkeleyone A (17) [18]. By employing a large-scale culture approach, asperanstinoid E (9) was obtained from the fungus Aspergillus calidoustus, which was isolated from wetland soil collected at Dianchi Lake [24]. Penicianstinoid D (10), an unusual austin-type meroterpenoid with a 6/6/6/6 tetracyclic skeleton containing an octahydro-2H-chromen-2-one unit, was obtained from Penicillium sp. TGM112 [23]. The endophytic fungus Penicillium sp. derived from the root of Panax notoginseng yielded three new ATMTs, including preaustinoid B1 (12), preaustiniod A1 (18), and A2 (19) [25] (Figure 2). Two additional meroterpenes were isolated and identified from rice cultures of Penicillium sp., a fungus obtained from the root bark of Melia azedarach. These new compounds were named preaustinoid B2 (13), and preaustinoid A3 (4) [26]. The undescribed meroterpenoid preaustinoid C (14) was isolated from Penicillium sp. RO-11, which was collected from the sediments of a hydrothermal spring located in the southwestern area of Saudi Arabia. Preaustinoid C showed significant activity against lipopolysaccharide (LPS)-induced NO production and a selective effect on IL-2 and IFN-γ gene regulation in activated Jurkat cells [27]. The mutant filamentous fungus Aspergillus nidulans has been found to produce protoaustinoid A (15) [17].

In addition, peniscmeroterpenoid N (20) was isolated from the marine-derived fungus Penicillium sclerotiorum GZU-XW03-2 [28], which was obtained from the intestinal tract of an Onchidium sp. collected from Xuwen in Guangdong province, China. The fungus Penicillium purpurogenum obtained from rotting fruit of the tree Averrhoa bilimbi growing in Sri Lanka yielded four new meroterpenoids, named dhilirolides F–I (21–24) [12]. In addition, 3,16-epoxy-preaustinoid D (25) is a rare austin meroterpenoid analogue with an open A ring that also features an undescribed oxygen bridge between C-3 and C-16 to construct an unexpected tetrahydrofuran ring; this was isolated and characterized from the fungus Aspergillus calidoustus [29].

Furthermore, two new meroterpenoids, namely, 1-methoxy-hydropreaustinoid A1 (26) and hydroberkeleyone B (27), have been isolated through the aid of Liquid Chromatograph Mass Spectrometer (LC-MS) from the sponge-derived fungus Eupenicillium sp. 6A-9, and both of them have immune-suppressive activities with IC₅₀ values of 42.3 and 28.5 μM, respectively [30]. Peniscmeroterpenoids F (28) and G (29) were also isolated from the marine-derived fungus Penicillium sclerotiorum GZU-XW03-2 [31]. SSW03M2 GY was isolated (4S, 5S, 7R, 9S, 11R, 12S)-1-methoxyberkeleyone C (30) from a Penicillium sp. that was derived from sediment at Seosan bay, South Korea; compound 30 showed anti-virulence activity by significantly inhibiting α-toxin (Hla) secreted by methicillin-resistant Staphylococcus aureus without growth inhibition at 10 μg/mL [32]. Peniscmeroterpenoids K–M (31–33) were also isolated from the marine-derived fungus Penicillium sclerotiorum GZU-XW03-2. Specifically, peniscmeroterpenoid K (31) was the first isolate where the C-24 was oxidized, and peniscmeroterpenoid M (33) (Figure 3) inhibited the production of nitric oxide (NO) in RAW264.7 cells with an IC₅₀ value of 48.04 ± 2.51 μM [28].

Preaustinoid D (34) was isolated from the endophytic fungus Penicillium sp. T2-8 associated with Gastrodia elata and showed moderate activity against Candida albicans with an MIC of 128 μg/mL [33]. Bioinformatics analysis of the gene clusters in association with the qRT-PCR detection revealed the amplification of two key genes (clusters A and B) for the sponge-associated fungus Penicillium brasilianum WZXY-m122-9. Chromatographic separation of the EtOAc extract from the large-scale fermentation of this fungal strain resulted in the isolation of two new ATMTs, namely, brasilianoids D and E (35–36) [34]. The marine-derived fungal isolate Penicillium sp. SF-5497 resulted in the isolation of two new meroterpenoids, named preaustinoid A6 (37) and preaustinoid A7 (38); furthermore, preaustinoid A6 (37) (Figure 4) inhibited protein tyrosine phosphatase-1B (PTP1B) in a noncompetitive manner, with a K_i value of 17.0 µM [35].

2.2. Pentacyclic Systems Austin-Type Meroterpenoids

2.2.1. Pentacyclic Systems-Rings A and B Are Spirocyclic—Typical Austin-Type Meroterpenoids

Austin (39) (Figure 5) is a novel ATMT isolated from a strain of Aspergillus ustus that was found on stored black-eyed peas (Vigna sinensis). Austin (39) showed the gross signs of toxicity in cockerels, such as a general listlessness followed either by eventual improvement (250 mg/kg, oral) or ataxia and death (375 mg/kg, oral) [3] (Figure 5). Austinol (40) and isoaustin (42) were isolated from an A. ustus strain [7]. Austinolide (41) and isoaustinone (44) are additional ATMTs produced by the rice cultures of Penicillium sp. [26]. Moreover, chemical examination of Aspergillus nidulans resulted the isolation of 11 β-hydroxyisoaustinone (43), (5′R)-isoaustinone (45), and neosuatinone (47) [17].

Neoaustin (46) was obtained from a soil isolate of Penicillium sp. MG-11 [36]. Moreover, ED-2 (48) was isolated from a strain of Emericella nidulans var. dentata, and ED-2 (48) was hydrogenated with H₂/PtO₂ and afforded the crystalline dihydro-derivative ED-2H (49) [6]. In addition, 11β-acetoxyisoaustinone (50) was isolated from the seagrass-derived fungus Pestalotiopsis sp. PSU-ES194 [37]. In the same year, 11β-acetoxyisoaustinone (50) was also isolated from Penicillium sp., an endophytic fungus obtained from Dysosma versipellis [38]. Bioinformatics analysis of the synthetic gene clusters in association with the qRT-PCR detection of the marine-derived Penicillium brasilianum WZXY-m122-9 isolate yielded four new ATMTs, namely brasilianoids G–I (51–53) and brasilianoid L (54) (Figure 5). Compound 54 showed cytotoxicity activity against RAW264.7, IEC-6, and A549 with IC₅₀ values of 84.67, 2.52 and 180.5 μg/mL, respectively [1].

Moreover, asperaustins A–C (55–57) were isolated from a marine-derived Aspergillus sp. Compound 55 possesses an unusual spiro[4.5]deca-3,6-dien-2-one moiety with a unique 5/6/6/6/5 pentacyclic skeleton [2] (Figure 6). Under the guidance of MS/MS-based molecular networking, 6-hydroxyisoaustinone (58) and 6-ketoisoaustinone (59) were isolated from the Penicillium sp. GDGJ-285 [39]. Penicianstinoid E (60), an unusual austin-type meroterpenoid that possesses a 6/5/6/6/6/5 fused hexacyclic skeleton with an uncommon five-membered ether ring system, was obtained from Penicillium sp. TGM112. Compound 60 showed inhibitory activity against newly hatched larvae of Helicoverpa armigera Hubner with an IC₅₀ value of 200 μg/mL [22]. Asperanstinoid A was obtained from the fungus A. calidoustus and has the same structure as penicianstinoid E (60) [24].

2.2.2. Pentacyclic Systems-Rings A and B Are Bicyclic Fused

Dhilirolide D (61), a member of the family of secondary metabolites with a putative meroterpenoid biogenetic origin and unprecedented dhilirane and isodhilirane carbon skeletons, was isolated from a laboratory culture of P. purpurogenum collected in Sri Lanka [13] (Figure 7). In addition, continued chemical investigation of laboratory cultures of P. purpurogenum yielded three new ATMTs, named dhilirolide E (62), dhilirolide K (63), and dhilirolide M (64) [12].

Chromatographic separation of the EtOAc extract of the large-scale fermentation of the sponge-associated P. brasilianum WZXY-m122-9 resulted in the isolation of three new ATMTs named brasilianoids A–C (65–67). Compound 65 showed significantly stimulated the expression of filaggrin and caspase-14 in HaCaT cells in dose-dependent manner; moreover, compounds 66 and 67 showed moderate inhibition against NO production in LPS-induced RAW 264.7 macrophages with IC₅₀ values of 37.69 ± 5.25 μM and 33.76 ± 3.13 μM, respectively [34] (Figure 7). Preaustinoids E–F (68–69) were isolated from the culture broth of a Penicillium sp. fungus collected from Chuja-do, Korea [40]. Asperaustin C (70) was isolated from a marine-derived Aspergillus sp. [2]. In addition, a new ATMT brasilianoid K (71) was isolated from the marine-derived fungus P. brasilianum WZXY-m122-9 [1].

2.3. Hexacyclic Systems Austin-Type Meroterpenoids

2.3.1. Hexacyclic Systems-Rings A and B Are Spirocyclic

A new ATMT isoaustinone (72) was isolated from a strain of Aspergillus variecolor, and it inhibited the growth of newly third-instar larvae of Aedes aegypti with an LC₅₀ value of 2.9 ppm [7] (Figure 8). Dehydroaustin (73) and dehydroaustinol (74) were isolated from a soil fungus of Penicillium sp. MG-11. Compound 74 showed antimicrobial activity against Escherichia coli with an MIC value of 250 μg/mL and inhibited the growth of newly third-instar larvae of Aedes aegypti with an LC₅₀ value of 7.3 ppm [36]. ED-1 (75) was isolated from a strain of Aspergillus ustus, and ED-1 (75) was hydrogenated with H₂/PtO₂ and afforded a crystalline dihydro derivative ED-1H (76) [41]. Acetoxydehydroaustin B′ (77) and 1,2-dihydro-acetoxydehydroaustin B′ (78) were isolated as a mixed crystal from the mangrove endophytic fungus Aspergillus sp. 085241B [42]. Furthermore, PF1364 (79) was isolated from Aspergillus sp. PF1364 and showed the control of pests and insects, such as the greenhouse whitefly [43].

2-Hydroacetoxydehydroaustin (80) was isolated from the mangrove endophytic fungus Aspergillus sp. 16-5c [44] (Figure 8). In addition, 1,2-dehydro-terredehydroaustin (81) was isolated from the mangrove endophytic fungus Aspergillus terreus and inhibited nitric oxide (NO) production with an IC₅₀ value of 42.3 μM [45]. Furanoaustinol (82) and 7-acetoxydehydroaustinol (83) (Figure 8) were isolated from the ethyl acetate extract of the marine-derived fungal strain Penicillium sp. SF-5497. Compound 82 weakly inhibited the activity of protein tyrosine phosphatase 1B in a dose-dependent manner with an IC₅₀ value of 77.2 μM. In addition, compound 83 weakly suppressed the overproduction of nitric oxide in lipopolysaccharide-challenged BV2 microglial cells with an IC₅₀ value of 61.0 μM [8].

Asperaustins A–B (84–85) (Figure 9) were isolated from a marine-derived Aspergillus sp. [2]. Brasilianoid J (86) was isolated from the marine-derived fungus P. brasilianum WZXY-m122-9 [27] (Figure 9). Penicianstinoids A–B (87-88) were obtained from the mangrove-derived fungus Penicillium sp. TGM112, and compounds 87 and 88 showed growth inhibition activity against newly hatched larvae of Helicoverpa armigera Hubner with IC₅₀ values of 200 μg/mL. Compounds 87 and 88 displayed activity against Caenorhabditis elegans with EC₅₀ values ranging from 9.4 ± 1.0 μg/mL to 38.2 ± 0.6 μg/mL [15]. In addition, 7-hydroxydehydroaustin (89) was isolated from the seagrass-derived fungus Pestalotiopsis sp. PSU-ES194 [37]. Austinone (90) was isolated from Penicillium sp. Y-5-2 [46].

Ustusaustin A (91) was isolated and identified from a culture extract of Aspergillus ustus TK-5, which obtained from the inner tissue of the ascidian Pyuramomus [47]. Three 3,5-dimethylorsellinic acid (DMOA)-based meroterpenoids, namely asperanstinoids B–D (92–94) (Figure 9), were obtained from the fungus Aspergillus calidoustus, which was isolated from wetland soil collected at Dianchi Lake [24]. Under the guidance of MS/MS-based molecular networking, three novel skeleton meroterpenoids, peniclactones A–C (95–97) (Figure 9), were isolated from Penicillium sp. GDGJ-285 [39]. Peniclactones A–C (95–97) represent the first meroterpenoids featuring a 6/5/6/6/5/6 (95), 6/5/6/6/5/5 (96), and 6/5/6/5/5/6 (97) hexacyclic ring systems, respectively. Bioassays showed that 97 inhibited nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophage cells with an IC₅₀ value of 39.03 μM.

2.3.2. Hexacyclic Systems-Rings A and B Are Bicyclic Fused

Dhilirolide L (98) and dhilirolide N (99) were isolated from P. purpurogenum, which was obtained from rotting fruit of a Averrhoa bilimbi tree growing in Sri Lanka. Compound 98 showed significant feeding inhibition and sublethal developmental disruption in the cabbage looper Trichoplusiani with a DC₅₀ value of 5.9 μg/cm² [12] (Figure 10). Brasilianoid F (100) was obtained from the large-scale fermentation of P. brasilianum WZXY-m122-9 [34].

2.4. Heptacyclic Systems Austin-Type Meroterpenoids

Heptacyclic Systems-Rings A and B Are Bicyclic Fused

Dhilirolides A–C (101–103) were isolated from laboratory cultures of the fruit-infecting fungus P. purpurogenum collected in Sri Lanka [13] (Figure 11). The fungus P. purpurogenum obtained from rotting fruit of a A. bilimbi tree growing in Sri Lanka yielded one new austin-type meroterpenoid, named dhilirolide J (104) [25].

3. Comprehensive Overview and Conclusions

To the best of our knowledge, investigations on the chemical constituents of ATMTs in the last five decades have reported fungal biodiversity, and total of 104 novel ATMTs from 5 genera of terrestrial- and marine-derived fungi have been reported in 40 research papers published from October 1976 to January 2023 (

Table 1. The compounds isolated from fungi (the structures of the compounds are illustrated in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10 and Figure 11).

Compound	Molecular Formula	Producer Strain	Habitat	Activity	Ref
ustinoneol A (1)	C24H30O6	Penicillium sp.	the root bark of Melia azedarach	NA b	[21]
preaustinoid A5 (2)	C26H32O7	Aspergillus nidulans	NR a	NA	[17]
preaustinoid A4 (3)	C26H32O7	Aspergillus nidulans	NR	NA	[17]
preaustinoid A3 (4)	C26H32O7	Aspergillus nidulans	NR	NA	[17]
		Penicillium sp.	the root bark of Melia azedarach	NA	[26]
austinoid C (5)	C26H32O6	Aspergillus oryzae NSAR1	NR	NA	[18]
penicianstinoid C (6)	C25H30O7	Penicillium sp. TGM112	the mangrove Brguiera sexangula var. rhynchopetala	inhibitory activity against newly hatched larvae of Helicoverpa armigera Hubner (IC50 = 100 μg/mL);	[22]
preaustinoid A (7)	C26H36O6	Penicillium sp.	the root bark of Melia azedarach	NA	[23]
preaustinoid C (8)	C26H34O6	Aspergillus oryzae NSAR1	NR	NA	[18]
asperanstinoid E (9)	C26H34O7	Aspergillus calidoustus	Dianchi Lake	NA	[24]
penicianstinoid D (10)	C29H40O7	Penicillium sp. TGM112	the mangrove Brguiera sexangula var. rhynchopetala	NA	[22]
preaustinoid B (11)	C26H36O6	Penicillium sp.	the root bark of Melia azedarach	NA	[23]
preaustinoid B1 (12)	C26H36O6	Penicillium sp.	the root bark of Melia azedarach	NA	[25]
preaustinoid B2 (13)	C24H34O5	Penicillium sp.	the root bark of Melia azedarach	NA	[26]
preaustinoid C (14)	C26H34O7	Penicillium sp. RO-11	the sediments of a hydrothermal spring	significant activity against LPS-induced NO production	[27]
protoaustinoid A (15)	C26H38O5	Aspergillus nidulans	NR	NA	[17]
5-hydroxyberkeleyone A (16)	C26H38O7	Aspergillus oryzae NSAR1	NR	NA	[18]
berkeleyone A (17)	C26H38O6	Aspergillus oryzae NSAR1	NR	NA	[18]
preaustinoid A1 (18)	C26H36O7	Penicillium sp.	the root bark of Melia azedarach	NA	[25]
preaustinoid A2 (19)	C26H34O7	Penicillium sp.	the root bark of Melia azedarach	NA	[25]
peniscmeroterpenoid N (20)	C26H34O8	Penicillium sclerotiorum GZU-XW03–2	the intestinal tract of the Onchidium sp.	NA	[28]
dhilirolide F (21)	C26H32O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
dhilirolide G (22)	C26H32O8	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
dhilirolide H (23)	C26H32O8	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
dhilirolide I (24)	C24H30O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
3,16-epoxy-preaustinoid D (25)	C26H36O8	Aspergillus calidoustus	Dianchi Lake	NA	[29]
1-methoxy-hydropreaustinoid A1 (26)	C27H40O8	Eupenicillium sp. 6A-9	the marine sponge Plakortis simplex	the immune-suppressive activities (IC50 = 42.3 μM)	[30]
hydroberkeleyone B (27)	C26H36O8	Eupenicillium sp. 6A-9	the marine sponge Plakortis simplex	the immune-suppressive activities (IC50 = 28.5 μM)	[30]
peniscmeroterpenoid F (28)	C26H34O7	Penicillium sclerotiorum GZU-XW03-2	the intestinal tract of the Onchidium sp.	NA	[31]
peniscmeroterpenoid G (29)	C26H36O8	Penicillium sclerotiorum GZU-XW03-2	the intestinal tract of the Onchidium sp.	NA	[31]
(4S, 5S, 7R, 9S, 11R, 12S)-1-methoxyberkeleyone C (30)	C27H36O7	Penicillium sp. SSW03M2 GY	a sediment at Seosan bay	significantly inhibited the production of α-toxin (Hla) by greater than 85% (at 10 μg/mL)	[32]
peniscmeroterpenoid K (31)	C26H34O8	Penicillium sclerotiorum GZU-XW03–2	the intestinal tract of the Onchidium sp.	NA	[28]
peniscmeroterpenoid M (32)	C26H34O8	Penicillium sclerotiorum GZU-XW03–2	the intestinal tract of the Onchidium sp.	NA	[28]
peniscmeroterpenoid L (33)	C27H38O8	Penicillium sclerotiorum GZU-XW03–2	the intestinal tract of the Onchidium sp.	inhibitory effects on NO production (IC50 = 48.04 ± 2.51 μM)	[28]
preaustinoid D (34)	C27H40O8	Penicillium sp. T2-8	fresh rhizomes of Gastrodia elata	antimicrobial (Candida albicans: 128 μg/mL);	[33]
brasilianoid D (35)	C26H38O7	Penicillium brasilianum WZXY-m122-9	sponge	NA	[34]
brasilianoid E (36)	C26H38O7	Penicillium brasilianum WZXY-m122-9	sponge	NA	[34]
preaustinoid A6 (37)	C26H38O8	Penicillium sp. SF-5497	sea sand	inhibited PTP1B activity with a Ki value of 17.0 μM)	[35]
preaustinoid A7 (38)	C26H36O7	Penicillium sp. SF-5497	sea sand	NA	[35]
austin (39)	C27H32O9	Aspergillus ustus	black-eyed peas (Vigna sinensis)	gross signs of toxicity in cockerels (listlessness: 250 mg/kg; death: 375 mg/kg)	[3]
austinol (40)	C25H30O8	Aspergillus ustus	NR	NA	[7]
austinolide (41)	C25H30O7	Penicillium sp.	the root bark of Melia azedarach	NA	[26]
isoaustin (42)	C27H32O9	Penicillium diversum	NR	NA	[7]
11β-hydroxyisoaustinone (43)	C25H30O7	Aspergillus nidulans	NR	NA	[17]
isoaustinone (44)	C25H30O6	Penicillium sp.	the root bark of Melia azedarach	NA	[26]
(5′R)-isoaustinone (45)	C25H30O6	Aspergillus nidulans	NR	NA	[17]
neoaustin (46)	C25H30O6	Penicillium sp. MG-11	soil	NA	[36]
neosuatinone (47)	C25H30O7	Aspergillus nidulans	NR	NA	[17]
ED-2 (48)	C25H30O8	Emericella nidulans var. dentata	NR	NA	[6]
ED-2H (49)	C25H32O8	Emericella nidulans var. dentata	NR	NA	[6]
11β-acetoxyisoaustinone (50)	C27H32O9	Pestalotiopsis sp. PSU-ES194	the seagrass Enhalus acoroides	NA	[37]
		Penicillium sp.	Dysosma versipellis	NA	[38]
brasilianoid G (51)	C25H28O7	Penicillium brasilianum WZXY-m122-9	sponge	NA	[1]
brasilianoid H (52)	C25H30O7	Penicillium brasilianum WZXY-m122-9	sponge	NA	[1]
brasilianoid I (53)	C25H28O8	Penicillium brasilianum WZXY-m122-9	sponge	NA	[1]
brasilianoid L (54)	C27H32O8	Penicillium brasilianum WZXY-m122-9	sponge	cytotoxicity (RAW264.1, IC50 = 84.67 μg/mL; IEC-6, IC50 = 2.52 μg/mL; A549, IC50 = 180.5 μg/mL)	[1]
asperaustin A (55)	C27H32O8	Aspergillus sp.	the brown alga Saccharina ichorioides f. sachalinensis	NA	[2]
asperaustin B (56)	C27H32O9	Aspergillus sp.	the brown alga Saccharina ichorioides f. sachalinensis	NA	[2]
asperaustin C (57)	C26H34O7	Aspergillus sp.	the brown alga Saccharina ichorioides f. sachalin ensis	NA	[2]
6-hydroxyisoaustinone (58)	C25H30O7	Penicillium sp. GDGJ-285	the traditional Chinese medicinal plant Sophora tonkinensis	NA	[39]
6-ketoisoaustinone (59)	C25H28O9	Penicillium sp. GDGJ-285	the traditional Chinese medicinal plant Sophora tonkinensis	NA	[39]
penicianstinoid E (60)	C27H32O10	Penicillium sp. TGM112	the mangrove Brguiera sexangula var. rhynchopetala	inhibitory activity against newly hatched larvae of Helicoverpa armigera Hubner (IC50 = 200 μg/mL)	[22]
asperanstinoid A (60)		Aspergillus calidoustus	Dianchi Lake	NA	[24]
dhilirolide D (61)	C25H30O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[13]
dhilirolide E (62)	C25H30O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
dhilirolide K (63)	C25H28O8	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
dhilirolide M (64)	C25H28O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
brasilianoid A (65)	C26H34O8	Penicillium brasilianum WZXY-m122-9	sponge	significantly stimulated the expression of filaggrin and caspase-14 in HaCaT cells	[34]
brasilianoid B (66)	C25H32O6	Penicillium brasilianum WZXY-m122-9	sponge	inhibitory effects on NO production (IC50 = 37.69 ± 5.25 μM)	[34]
brasilianoid C (67)	C25H32O6	Penicillium brasilianum WZXY-m122-9	sponge	inhibitory effects on NO production (IC50 = 33.76 ± 3.13 μM)	[34]
preaustinoid E (68)	C25H32O6	Penicillium sp. FCH061	sediment samples	NA	[40]
preaustinoid F (69)	C25H32O6	Penicillium sp. FCH061	sediment samples	NA	[40]
asperaustin C (70)	C25H32O6	Aspergillus sp.	the brown alga Saccharina cichorioides f. sachalinensis	NA	[2]
brasilianoid K (71)	C25H32O7	Penicillium brasilianum WZXY-m122-9	sponge	NA	[1]
dehydroaustin (72)	C27H30O9	Aspergillum variecolor	NR	growth inhibitory activity against the third-instar larvae of Aedes aegypti (LC50 = 2.9 ppm)	[7]
dehydroaustinol (73)	C25H28O8	Penicillium sp. MG-11	soil	NA	[36]
acetoxydehydroaustin (74)	C29H32O11	Penicillium sp. MG-11	soil	antimicrobial activity (Escherichia coli: 250 μg/mL); growth inhibitory activity against the third-instar larvae of Aedes aegypti (LC50 = 7.3 ppm)	[36]
ED-1 (75)	C25H28O8	Emericella dentata	NR	NA	[41]
ED-1H (76)	C25H30O8	Emericella dentata	NR	NA	[41]
acetoxydehydroaustin B′ (77)	C29H32O11	Aspergillus sp. 085241B	the Shankou Mangrove National Nature Reserve	NA	[42]
1,2-dihydro-acetoxydehydroaustin B′ (78)	C29H34O11	Aspergillus sp. 085241B	the Shankou Mangrove National Nature Reserve	NA	[42]
PF1364 (79)	C31H36O13	Aspergillus sp. PF1364	NR	control of pest and insect, such as the greenhouse whitefly	[43]
2-hydroacetoxydehydroaustin (80)	C29H34O12	Aspergillus sp. 16-5c	Sonneratia apetala	NA	[44]
1,2-dehydro-terredehydroaustin (81)	C32H38O11	Aspergillus terreus H010	Kandelia obovata	inhibitory effects on NO production (IC50 = 42.3 μM)	[45]
furanoaustinol (82)	C25H30O9	Penicillium sp. SF-5497	sea sand	inhibited the activity of protein tyrosine phosphatase 1B in a dose-dependent manner (IC50 = 77.2 μM)	[8]
7-acetoxydehydroaustinol (83)	C27H30O10	Penicillium sp. SF-5497	sea sand	inhibitory effects on NO production (IC50 = 61.0 μM)	[8]
asperaustin A (84)	C27H32O8	Aspergillus sp.	the brown alga Saccharina cichorioides f. sachalinensis	NA	[2]
asperaustin B (85)	C27H32O9	Aspergillus sp.	the brown alga Saccharina cichorioides f. sachalinensis	NA	[2]
brasilianoid J (86)	C27H30O10	Penicillium brasilianum WZXY-m122-9	sponge	NA	[1]
penicianstinoid A (87)	C31H36O12	Penicillium sp. TGM112	Bruguiera sexangula var. rhynchopetala	inhibition activity against newly hatched larvae of Helicoverpa armigera Hubner (IC50 = 200 μg/mL); insecticidal activity against C. elegans (EC50 = 9.4 ± 1.0 μg/mL)	[15]
penicianstinoid B (88)	C25H28O9	Penicillium sp. TGM112	Bruguiera sexangula var. rhynchopetala	inhibition activity against newly hatched larvae of Helicoverpa armigera Hubner (IC50 = 200 μg/mL); insecticidal activity against C. elegans (EC50 = 9.9 ± 0 μg/mL)	[15]
7-hydroxydehydroaustin (89)	C27H30O10	Pestalotiopsis sp. PSU-ES194	the seagrass Enhalus acoroides	NA	[37]
austinone (90)	C32H40O13	Penicillium sp. Y-5-2	NR	NA	[46]
ustusaustin A (91)	C34H36O11	Aspergillus ustus TK-5	the marine ascidian Pyuramomus	neuraminidase inhibitory activity (IC50 = 5.28 μM)	[47]
asperanstinoid B (92)	C31H36O13	Aspergillus calidoustus	Dianchi Lake	NA	[24]
asperanstinoid C (93)	C32H38O12	Aspergillus calidoustus	Dianchi Lake	NA	[24]
asperanstinoid D (94)	C27H30O9	Aspergillus calidoustus	Dianchi Lake	NA	[24]
peniclactone A (95)	C26H28O9	Penicillium sp. GDGJ-285	the traditional Chinese medicinal plant Sophora tonkinensis	NA	[39]
peniclactone B (96)	C25H28O8	Penicillium sp. GDGJ-285	the traditional Chinese medicinal plant Sophora tonkinensis	NA	[39]
peniclactone C (97)	C26H28O8	Penicillium sp. GDGJ-285	the traditional Chinese medicinal plant Sophora tonkinensis	inhibitory effects on NO production (IC50 = 39.03 μM)	[39]
dhilirolide L (98)	C25H28O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	against the cabbage looper Trichoplusia ni (DC50 = 5.9 μg/cm2)	[12]
dhilirolide N (99)	C25H26O8	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]
brasilianoid F (100)	C25H32O7	Penicillium brasilianum WZXY-m122-9	sponge	NA	[34]
dhilirolide A (101)	C25H28O9	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[13]
dhilirolide B (102)	C25H28O8	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[13]
dhilirolide C (103)	C25H28O8	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[13]
dhilirolide J (104)	C25H28O7	Penicillium purpurogenum	Averrhoa bilimbi fruit	NA	[12]

^a Not reported. ^b No activity reported in the reference.

, Figure 12, Figure 13, Figure 14 and Figure 15). In total, 37% of the compounds are categorized as the tetracyclic type (up to 38 compounds) followed by pentacyclic (32%, 33), hexacyclic (27%, 29), and heptacyclic (4%, 4) types (Figure 12). This review summarizes the source, chemistry, and biological activities of the novel ATMTs. The majority of the ATMTs have been isolated since 2010, accounting for about 80% of all reported ATMTs (83/104) and 75% of the published articles (Figure 13). The increase was largely due to improvements in isolation procedures. All of the published ATMTs that have been isolated and identified in various filamentous fungi, most of them were produced by Penicillium (62%) and Aspergillus (30%), representing more than 90% of the secondary metabolites reported (Figure 14). The remaining (about 10%) were produced by Pestalotiopsis (2%), Eupenicillium (2%), and Emericella (4%).

In terms of the source distribution of compounds, one surprising discovery was that all of these novel ATMTs were isolated from fungi, including 39% terrestrial- and 43% marine-derived endophytic fungi, much more than those produced by unknown sources (18%) (Figure 15). The results showed that these kinds of ATMTs are a very special class of fungi metabolites, and more chemical ecological research needs to be carried out. Overall, this review provides a comprehensive overview of the diverse chemical structures and bioactive properties of 104 new ATMTs that have been isolated from fungi in the last five decades. Nearly 26% of the ATMTs showed bioactivities. About 7% exhibited inhibitory effects on NO production. Interestingly, about 9% ATMTs have been showed to possess selective insecticidal activity, about 2% exhibit antimicrobial activity, and 8% demonstrate other activities, including cytotoxicity and antityrosinase activity (Figure 16), revealing the untapped potential of activity ATMTs in pesticides and medicinal applications. However, for most of the isolated ATMTs, the lack of activity analysis and pharmacodynamic evaluation limit their application.

In summary, a total 104 of ATMTs have been isolated and characterized to date since the initial discovery of austin-type meroterpenoids in 1976. Although ATMTs have a distinct a unique chemical skeleton and potential biological activities, the unavailability of large amounts of natural austin-type meroterpenoids and purification challenges due to their structural complexity hindering efficient chemical synthesis have hindered further research. Most of the ATMTs with novel skeletons and biological activities have been discovered in recent years. The further development and application of these compounds is important, and the identification of promising lead compounds for the development of drugs is a critical future direction of study.