Recent Advances in Chemistry and Bioactivities of Secondary Metabolites from the Genus Acremonium

Acremonium fungi is one of the greatest and most complex genera in Hyphomycetes, comprising 130 species of marine and terrestrial sources. The past decades have witnessed substantial chemical and biological investigations on the diverse secondary metabolites from the Acremonium species. To date, over 600 compounds with abundant chemical types as well as a wide range of bioactivities have been obtained from this genus, attracting considerable attention from chemists and pharmacologists. This review mainly summarizes the sources, chemical structures, and biological activities of 115 recently reported new compounds from the genus Acremonium from December 2016 to September 2023. They are structurally classified into terpenoids (42%), peptides (29%), polyketides (20%), and others (9%), among which marine sources are predominant (68%). Notably, these compounds were primarily screened with cytotoxic, antibacterial, and anti-inflammatory activities. This paper provides insights into the exploration and utilization of bioactive compounds in this genus, both within the scientific field and pharmaceutical industry.


Introduction
Natural products and their structural analogues have historically played a vital role in the drug discovery and development process, especially for cancer and infectious diseases [1,2].Fungi are a hyper-diverse kingdom of life, with millions of species estimated to be present worldwide, and less than 10% of which have been described taxonomically.Of all the described and undescribed fungi, only 7% have been investigated for the chemistry of secondary metabolites [3].Meanwhile, the secondary metabolites of filamentous fungi are largely untapped, owing to the magnitude of biosynthetic gene clusters combined with the historic number of sequenced genomes [4].
The Acremonium fungi, belonging to the Hypocreataceae family, is one of the greatest and most complicated genera in Hyphomycetes [5].It is also a common and widely distributed fungus with about 130 species.According to the ecological habits and nutritional methods of the fungus, it is mainly divided into saprophytic, plant-parasitic, and authigenic types, and it can also survive in terrestrial or marine environments [6], but also live in close association with soil [7], plants [8], sponge [9], coral [10], algae [11], and holothurian [12], etc. Phylogenetic studies showed that the sources of Acremonium were related to at least three kinds of ascomycete fungi, Hypocreaceae, Ergotaceae, and Chaetomium [13].
As of July 2016, 356 compounds, including steroids, terpenoids, meroterpenoids, polyketides, alkaloids, peptides, and miscellaneous types, have been isolated from the genus Acremonium [14].These compounds displayed a wide range of biological activities comprising antimicrobial, antitumor, immunosuppressive, antioxidant, and anti-inflammatory activities [14].Notably, a series of ascochlorin derivatives isolated from A. sclerotigenum in our recent study were characterized as novel potent hDHODH inhibitors for the further development of anticancer agents [10].The diverse and bioactive secondary metabolites from Acremonium have continued to attract great attention from chemists and pharmacologists.
The Acremonium fungi are producers of structurally diverse and pharmacologically active compounds.In this review, a total of 271 secondary metabolites (Known ones were summarized in Table S1), including 115 new compounds, were recently obtained from the genus Acremonium from December 2016 to September 2023.Structurally, they were classified into terpenoids (124 compounds), polyketides (66 compounds), peptides (45 compounds), steroids (18 compounds), alkaloids (9 compounds), and amides (9 compounds).Among them, 101 compounds displayed a wide range of biological activities, including antimicrobial, cytotoxic, anti-inflammatory, insecticidal, and enzyme inhibition activities.This review summarizes the sources, chemical structures, and biological activities of 115 new compounds reported in the genus Acremonium from December 2016 to September 2023.
One new sesquiterpenoid, marinobazzanan (16), was isolated from marine sedimentderived Acremonium sp.CNQ-049, which showed an inhibition of cancer cell migration and invasion at non-toxic concentrations of 1, 2.5, and 5 µM by down-regulating transcription factors of Snail, Slug, and Twist.In addition, marinobazzananan reduced cell motility by down-regulating the expression level of KITENIN and by up-regulating the expression level of KAI 1, and it further reduced the number of metastatic nodules in the intraperitoneal xenograft mouse model [16].Moreover, one new acorane-type sesquiterpene glycoside, isocordycepoloside A (17), was isolated from the fungus Acremonium sp.SF-7394 [17].

Meroterpenoids
Twenty-five ascochlorin derivatives, biosynthesized through the farnesylation of orsellinic acid [19], were obtained from the coral-derived A. sclerotigenum GXIMD 02501, including 13 new compounds, acremochlorins A-M (32-44) (Figure 3).Compounds 32 and 44, two novel potent human dihydroorotate dehydrogenase (hDHODH) inhibitors, induced the apoptosis of triple-negative breast cancer (TNBC) cells by up-regulating the levels of cleaved-PARP1 and cleaved-caspase7, and further effectively inhibited tumor growth in a patient-derived TNBC xenograft model without significant weight loss or obvious toxicity in mice, showing higher safety than that of brequinar [10].
Meanwhile, ascofuranone and ascochlorin, two representative ascochlorin derivatives, were also reported as potential lead candidates for drug development targeting the hDHODH of cancer cells living under a tumor microenvironment [20].Moreover, two known potential anti-tumor ascochlorins, 3-bromoascochlorin (BAS) and ilicicolin A (Ili-A), were also obtained from the coral-derived fungus A. sclerotigenum GXIMD 02501.BAS could induce the apoptosis, invasion, and migration of H446 and H69AR cells, and it further suppressed the tumor growth of a small cell lung cancer xenograft mouse model by inhibiting the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway [21].Moreover, Ili-A showed efficacious activity against prostate cancer cells by abrogating EZH2/AR-mediated processes and demonstrated a synergistic anti-prostate cancer effect combined with enzalutamide in vivo, revealing a novel EZH2 inhibitor for the treatment of castration-resistant prostate cancer [22].Ascofuranone and its derivatives, obtained from A. egyptiacum, were found as the first dual inhibitors of fumarate and oxygen respiration in Echinococcus multilocularis by targeting mitochondrial complexes II and III, suggesting potential lead compounds in the development of anthelminthic drugs [23].One new ascochlorin, acremochlorin N (45), and a pair of new natural enantiomers, 3-phenylcyclopentane-1,2-diol (±-46) (Figure 4), together with nine known analogues were isolated from marine sediment-derived A. furcatum CS-280.All the isolates showed significant anti-Vibrio activities, especially against Vibrio harveyi and V. alginolyticus.Moreover, the presence of chlorine atoms in the ascochlorins could significantly enhance their antibacterial activity [24].Meanwhile, four known ascochlorins, including ascochlorin, 10 ′ -deoxy10 ′ α-hydroxy ascochlorin, 4 ′ ,5 ′ -dihydro-4 ′ -hydroxyascochlorin, and ascofuranone, were obtained from the sponge-derived Acremonium sp.IMB18-086.Ascochlorin and ascofuranone showed significant antibacterial activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, and Candida albicans.Moreover, they showed significant cytotoxicity against A549 and/or HepG2 cell lines with IC 50 values of 0.9-5.8µM [25].
Acremine S (47) was isolated from the sponge Mycale sp.derived fungus A. persicinum KUFA 1007 and showed inhibitory activity against butyrylcholine esterase, which was three folds higher than that of galantamine [26].Hexahydroacremonintriol (48), along with an analogue, acremonin A glucoside, were obtained from a tropical sinkhole derived from A. masseei CICY026.Both displayed insecticidal activity against Myzus persicae and/or Rhopalosiphum padi with settling inhibition ranging from 48% to 67% [27].One new fusidic acid derivative, acremonidiol A (49), and three known analogs were obtained from the endophytic fungus A. pilosum F47.Among these, fusidic acid displayed a strong inhibitory effect on Gram-positive bacterium S. aureus, and the acetylation of the hydroxyl group at C-16 was crucial for antibacterial activity [28].

Peptides
A total of 45 peptides have been reported from Acremonium fungi during the period 2016-2023, including 33 new compounds, while 19 bioactive compounds were found.

Polyketides
A total of 60 polyketides have been reported from the genus Acremonium within the period, including 23 new compounds and 18 bioactive compounds.
Most of them inhibited LPS-induced NF-κB activation in RAW 264.7 cells at a concentration of 20 µM.Notably, compounds 91 and 92 showed inhibitions of RANKL-induced osteoclast differentiation in bone marrow macrophages without cytotoxicity [40].
The sterol 3β,5α,6β,7α-tetrahydroxyergosta-8( 14),22-diene was isolated from the liquid culture of A. persicum.Its antiproliferative potential was found to be comparable to or even stronger than that of commonly used anticancer drugs in breast cancer and colon cancer cell lines T-47 D and WiDr [49].

Amides
A total of nine amides have been discovered from the genus Acremonium during the period 2016-2023, including four new compounds and three bioactive compounds.

Alkaloids
A total of nine alkaloids have been reported from the genus Acremonium during the period 2016-2023, including two new compounds and three bioactive compounds.

Comprehensive Overview and Conclusions
In this review, the sources, structural diversity, and biological activity of secondary metabolites from Acremonium fungi are summarized covering a period of time comprising the period between Dec 2016 and Sep 2023.A total of 271 compounds were obtained from the genus Acremonium.Among them, 115 were characterized as new compounds (42%) (Table 1).Notably, 169 compounds were predominantly marine-sourced and 77 ones were characterized as new compounds, accounting for nearly 67% of all new compounds.Most of the reviewed Acremonium fungi were isolated from marine habitats or terrestrial sources.Remarkably, the top three marine sources of these reviewed Acremonium fungi were sediments (22%), corals (16%), and sponges (12%) (Figure 13).The chemical structures of the 115 recently reported secondary metabolites from Acremonium fungi can mainly be classified into four types, including terpenoids (46%), polyketides (24%), peptides (17%), and others (13%) consisting of steroids, amides, and alkaloids (Figure 14).However, among these 115 new compounds, terpenoids predominantly accounted for 42%, while polyketides, peptides, and other types accounted for 20%, 29%, and 9%, respectively.Moreover, it is worth noting that nearly 37.3% (101 compounds) showed broad-spectrum biological activities, including insecticidal, antibacterial, cytotoxic, enzyme inhibition, antiviral, anti-inflammatory, antioxidant, and antimalarial activities.Notably, antibacterial (35.6%), cytotoxic (35.6%), and anti-inflammatory (10.9%) represent the top three bioactivities.In summary, widely distributed Acremonium fungi have hitherto been proven to be vital sources of novel and diverse secondary metabolites with a broad range of biological activities, revealing their great untapped potential in medicinal, agrochemical, and industrial applications.However, for most of these isolated compounds, the lack of deep pharmacological mechanisms as well as comprehensive pharmacokinetic evaluation limit their applications.Overall, this review will shed light on the further pharmacological investigation and medicinal utilization of these valuable secondary metabolites from this genus and will continuously arouse high interest in natural product chemistry, synthetic chemistry, pharmacology, and medicinal chemistry.

2. 4 .
Steroids, Amides, or Alkaloids 2.4.1.Steroids A total of eighteen steroids have been discovered from the genus Acremonium during the period 2016-2023, including four new compounds as well as five bioactive compounds.

Figure 13 .
Figure 13.The habitat distribution of these reviewed Acremonium fungi from December 2016 to September 2023.

Figure 14 .
Figure 14.The structural diversity (left) and bioactivities (right) of secondary metabolites in Acremonium fungi from December 2016 to September 2023.

Table 1 .
Recently reported new compounds from the genus Acremonium (December 2016 to September 2023).