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Abstract

Fungal bioactive secondary metabolites are considered promising sources for the production of unique compounds with exceptional chemical structures. Of these bioactive secondary metabolites, meleagrins are prenylated indole alkaloids characterized by a triazaspirocyclic skeleton that is generally obtained from Penicillium species. Meleagrins are alkaloids with promising biological activities. Here is a survey of previously published research on meleagrins: their sources, biosynthetic pathways, synthesis, and bioactivities.

Keywords

meleagrins biosynthetic gene cluster synthesis bioactivity

Introduction

Fungi isolated from marine environments are recently considered as potential sources for the production of unique bioactive secondary metabolites leading to the isolation of lead compounds for drug discovery.^1,2 Fungal secondary metabolites have exhibited significant applications in agriculture and the pharmaceutical industry, as well as the food industry, and have played a crucial economical role.^1,3-5 Penicillium spp are the most known producers of biologically active byproducts.^6,7 Meleagrins are considered as one of the most reported active compounds obtained from Penicillium spp^8,9 (Figure 1).

Figure 1.

Chemical structure of meleagrins. doi: 10.1002/chem.201501150.¹⁰

Meleagrin A (1), (3E, 7Ar, 12As)-7a-(1,1-dimethyl-2-propen-1yl)-7a,12-dihydro-6-hydroxy-3-(1H-imidazol-5-ylmethylene)-12-methoxy-1H,5H-imidazo[1′2′:1,2]pyrido[2,3 -b]indole-2,5(3H)-dione is a prenylated indole alkaloid having a triazaspirocyclic skeleton.¹¹ Meleagrin B (2) is a unique complex molecule of meleagrin A, in which the imidazole moiety is substituted with a diterpene side chain, whereas meleagrins C-E (3-5) have special acetate–mevalonate-derived side chains on the imidazole core.⁹

Meleagrins have been detected in over 30 Penicillium spp (Table 1). Further, meleagrin A (1) has been isolated from two other sources, Meleagris gallopavo¹² and Emericella dentata Nq45.^13,14

Table 1.

Penicillium spp. as Sources of Meleagrins.

Penicillium species	Sources
Penicillium meleagrinum ¹⁵	IFO 8143, Institute for Fermentation, Osaka, Japan
Penicillium rivulum Frisvad (IBT 24420)¹⁶	IBTCC, BioCentrum-DTU, Denmark
Penicillium tulipae ¹⁷	IBTCC, BioCentrum-DTU, Denmark
Penicillium oxalicum F30^18,19	Oceanic deposits (Caulerpa sp.)
Penicillium chrysogenum strain DS54555^20,21
P. chrysogenum strain F717²²	Seaside mucus, Daechun Beach, Korea
P. chrysogenum ²³	Liagora viscida, Rass Mohamed, Red Sea, Egyptian
Penicillium commune QSD-17²⁴	Marine settlements, South China
P. commune SD-118*²⁵	Deep-sea Deposits, South China
P. chrysogenum IFL1 and IFL2²⁶	Mycology, Lab. Biochem. Appl. Microbiol., (UFRGS), Brazil
Penicillium sp., strain GD6²⁷	Chinese mangrove, Bruguiera gymnorrhiza, Zhanjiang coast, China
P. chrysogenum strain S003^11,28	Red Sea sediment, Saudi Arabia
P. chrysogenum ²⁹	Endophytic P. chrysogenum derived from olive tree leaves, Egypt
Penicillium sp. YPGA11³⁰	Deep-sea residues, Yap Trench, West Pacific Ocean
Penicillium sp. F23-2⁹	Deep-sea remains, Shanghai, China

Meleagrins possess various biological characteristics including inhibition of the biosynthesis of bacterial type II fatty acid,^22,31 antiproliferative activity,^9,13,29,30 inhibiting the polymerization of tubulin in Jurkat cells, and a protection effect against bleomycin-induced pulmonary fibrosis in mice.¹¹

In the present review, we describe the different sources of meleagrins, their biosynthetic and synthetic pathways, as well as their biological activities for the first time.

Biosynthetic Pathway of Meleagrins

Enzymes catalyze the biosynthesis of secondary metabolites in fungi. Gene clusters encode these enzymes, which are frequently coregulated at the transcriptional level.³² Gene clusters can be created by de novo assembly of specific genes from other cellular functions. Still, new gene clusters are also formed through the reorganization of progenitor clusters and distributed by horizontal gene transfer.³²

Roquefortine/Meleagrin Gene Cluster

The roquefortin/meleagrin gene cluster in the Penicillium chrysogenum genome underwent a series of RNA silencing experiments, which enabled a putative biochemical mapping of each step of the biosynthetic pathway.^33,34

García-Estrada et al investigated the biosynthetic pathway of the mycotoxins roquefortine C/meleagrin originated from a single path in P. chrysogenum through a single gene cluster.²⁰ This cluster includes Pc21g15480, Pc21g15430, Pc21g15460, Pc21g15470, Pc21g15450, and Pc21g15440 genes (Scheme 1).

Scheme 1.

Roquefortine C/meleagrin pathway in Penicillium chrysogenum. The arrow with the symbol (×) refers to the silenced steps.

Pc21g15430 (rpt) encodes the prenyltransferase enzyme required for the biosynthesis of roquefortine C (11) and meleagrin (1). Furthermore, silencing of either Pc21g15460 or Pc21g15470 gene cluster caused diminution in roquefortine C (11) and meleagrin A (1). On the other hand, silencing of Pc21g15440 (gmt), methyltransferase gene, led to an accumulation of glandicolin B (13), demonstrating that this enzyme catalyzes the transformation of glandicolin B (13) to meleagrin A (1).²⁰

Driessen and his coworkers described the biosynthetic process used in the filamentous fungus P. chrysogenum to produce meleagrin A and other correlated chemical compounds.²¹ Histidyl-tryptophanyl-diketopiperazine (HTD), dehydro-histidyl-tryptophanyl-diketopiperazine (DHTD), roquefortine D, roquefortine C, glandicoline A, and glandicoline B were detected as abundant metabolites of this route.

Each stage of an enzymatic reaction was assigned by a specific set of genes. L-tryptophan (6) and L-histidine (7) were delivered as substrates by the nonribosomal peptide synthetase (RoqA), which results in the formation of HTD. Oxidation of HTD (8) by oxidoreductase (RoqR) provided DHTD (14) through the cytochrome P450 process. Prenylation of both HTD (8) and DHTD (14) via dimethylallyl tryptophan synthetase (RoqD) produced roquefortine D (10) and roquefortine C (11) without the involvement of any suggested intermediates. Roquefortine C (11) was transformed into glandicoline B (13) through the intermediate glandicoline A (12) with the help of (RoqM) and (RoqO), two monooxygenases that have been mixed in the former trial to explore the biosynthetic pathway. Eventually, glandicoline B (13) was converted to meleagrin A (1) through a methyltransferase (RoqN) (Scheme 2).

Scheme 2.

Roquefortin/meleagrin biochemical pathway for meleagrin biosynthesis.

In another publication, Driessen and his coworkers endorsed the roquefortin C/meleagrin biochemical pathway for meleagrin A (1) biosynthesis.³⁵

Oxaline Biosynthetic Gene Cluster

Sherman and his coworkers reported the Oxa gene cluster from the fungus Penicillium oxalicum F30 alongside the representation of OxaD, a flavin-dependent oxidase that creates roquefortine L (15). Oxa D is considered as a nitrone-bearing intermediate in the biogenesis of meleagrin A (1) and then the biogenesis of oxaline (17) (Scheme 3).^19,36

Scheme 3.

The Oxa gene cluster from the fungus Penicillium oxalicum F30.

Acetate–mevalonate Pathway

Du et al postulated a biosynthetic pathway of meleagrin D (4) and meleagrin E (5) from meleagrin A (1). They postulated that the diterpene side chain of both meleagrin D (4) and meleagrin E (5) originated from six acetates via the acetate-mevalonate pathway.⁹ Intermolecular Michael addition of either 6-hydroxy-2,6-dimethylhept-2-en-4-one (I) or 2,6-dimethylhepta-2,5-dien-4-one (II) to meleagrin A (1), for which the biosynthetic pathway has been well established,^37,38 provided meleagrin D (4) and meleagrin E (5), respectively (Scheme 4).

Scheme 4.

Biosynthetic pathway of meleagrins D and E.

Synthetic Pathway of Meleagrin A (1)

Sunazuka and his coworkers synthesized meleagrin A (1) via the transformation of neoxaline (19) using the two-step Albright–Goldman reaction conditions: the oxidation of neoxaline (19) and then the hydrolysis of the acyloxy group with sodium hydrogen carbonate in methanol¹⁰ (Scheme 5).

Scheme 5.

Synthesis of meleagrin A (1) by neoxaline transformation.

Meleagrin A (1) Derivatives

Some meleagrin derivatives were obtained via chemical modification of some functional groups such as the hydroxyl and amine groups of meleagrin A (Scheme 6).²² As a result of the demethoxylation of compound 1, glandicolin A (12) and bromo-glandicolin A (20) were produced. Oxaline (17), N¹⁴-methylmeleagrin (21), and O,N¹⁴-dimethylmeleagrin (22), were produced by the methylation of compound 1. On the other hand, methylation of compound 12 resulted in O,N¹⁴-dimethylglandicolin (23)²² (Scheme 6).

Scheme 6.

Some derivatives of meleagrin A (1).

Biological Activities

Meleagrin A (1) has been recognized as a distinct inhibitor of Staphylococcus aureus FabI.²² Its activity could be explained by a direct connection with S. aureus FabI in a fluorescence quenching assay, which led to the inhibition of fatty acid biosynthesis and the progression of S. aureus. It also stepped up the minimum inhibitory concentration for FabI-overexpressing S. aureus.

On the other hand, meleagrin A (1) was not effective against the isoform of FabK, but inhibited the growth of Staphylococcus pneumonia, although S. pneumonia has a FabK isoform. In addition, meleagrin A (1) did not show resistant mutants toward S. aureus, as well as Escherichia coli.²² Thus these results demonstrated that meleagrin A (1) may have the potential to be used as a lead compound for the treatment of bacteria that show drug resistance and promising anti-MRSA, besides being selected as an inhibitor of S. aureus FabI.

In another publication, the efficacy of meleagrin A (1) as an antimicrobial agent has been confirmed against Aspergillus niger, Bacillus subtilis, and B. megaterium, with moderate activity. The best effectiveness was against Candida albicans, with an inhibition zone of 15 ф mm.²³

Additionally, meleagrin A (1) showed inhibition of the biosynthesis of bacterial type II fatty acid, while meleagrin B (2) was recorded to be an inhibitor of tubulin polymerization in Jurkat cells.^22,31

Meleagrin A (1) has been reported to have favorable antisettlement biological activity against cyprids of Amphibalanus amphitrite with a half maximal effective concentration (EC₅₀ = 1.10 μg/mL).³⁹ This study confirmed that meleagrin A is a potential nontoxic antifoulant.³⁹

Subsequent studies were conducted to investigate the influence of meleagrin on the life cycle of A. amphiplanus as a causative agent of marine fouling.⁴⁰ Fifty proteins have been characterized by applying isobaric tags for relative and absolute quantitation coupled with 2D LC−MS/MS proteomic analysis to investigate the effect of meleagrin on the proteomic expression profile of cyprid development and aging in the barnacle Balanus amphitrite. It was found that 50 proteins of B. amphitrite were differentially expressed in response to meleagrin treatment: 26 proteins were associated with development/aging in the cypris larvae, and, of those, 24 were associated specifically with meleagrin treatment.⁴⁰ Analysis of data from the Kyoto Encyclopedia of Genes and Genomes indicated that meleagrin affected several pathways, including metabolic pathways, extracellular matrix–receptor interactions, and the regulation of the actin cytoskeleton. Among the 24 proteins affected by meleagrin treatment, a vitellogenin-like protein was upregulated, indicating endocrine disruption and prevention of the larval molting cycle. With the exception of mediation of the molting process involving chitin-binding proteins and adenosine triphosphatase (ATPase)-mediated energy, most of the major proteins in this study were not found to be significant in butenolide and polyether B-treated larvae, suggesting that meleagrin exhibits a distinct and specific mode of action.⁴⁰

Meleagrin A (1), isolated from Penicillium commune SD-118*, was evaluated against a human prostate cancer cell line (DU-145) and showed effective cytotoxic activity (IC₅₀ = 5.0 µg/mL). The compound demonstrated moderate cytotoxicity toward cell lines in the order: MDA-MB-231 (IC₅₀ = 11.0 µg/mL) > HepG2 (IC₅₀ = 12.0 µg/mL) > HeLa (IC₅₀ = 20.0 µg/mL) > NCIH460 (IC₅₀ = 22.0 µg/mL).²⁵

Meleagrin A (1) showed interesting and distinct activity against a panel of breast cancer cell lines including MDA-MB-231, MDA-468, BT-474, SKBR-3, MCF7, and MCF7-dox with IC₅₀ values ranging from 1.9 to 8.9 µM.²⁹ Meleagrin A (1) exhibited ATP competitive protein tyrosine kinases-Met (c-Met) inhibitory activity.²⁹ This observation was assured through molecular docking studies.²⁹ Treating breast cancer cells with meleagrin also inhibited cell migration and invasion under growth hormone induction. The in vivo assay demonstrated that meleagrin A (1) suppresses the progression of the spread of triple-negative adenocarcinoma cells in nude mouse models.²⁹

Moreover, meleagrin A (1) from Penicillium sp. YPGA11 showed antiproliferative activity against a panel of human esophageal carcinoma cells, EC109, EC9706, KYSE30, KYSE70, and KYSE450, with IC₅₀ values of 31.33 ± 0.77, 32.93 ± 0.20, 40.56 ± 3.24, 36.93 ± 1.87, and 25.03 ± 1.20 µM, respectively.³⁰

In 2021, Hamed et al reported that meleagrin A (1), obtained from E. dentata Nq45, exhibited effective cytotoxic activity toward KB-3-1, a human cervix carcinoma (IC₅₀ = 3.07 μmol/L), besides its activity against multidrug-resistant subclone (IC₅₀ = 6.07 μmol/L).¹³

In two successive studies by Du et al in 2009 and 2010, concerning the activity of melaegrins A (1) and B (2) as anticancer agents, they found that the isolated meleagrin B (2) from Penicillium sp. F23–2 showed cytotoxic activity against a number of different tumor cell lines, namely HL-60, A-549, MOLT-4, and BEL-7402 with IC₅₀ values ranging from 1.8 to 6.7 µM.⁴¹ Meleagrin A (1) showed mild effectiveness against the nonsmall cell lung cancer A-549 cell (IC₅₀ = 19.9 µM), besides the leukemia HL-60 cell line (IC₅₀ = 7.4 µM).⁹ The cytotoxic mechanisms of melaegrins A (1) and B (2) were investigated by flow cytometric studies.⁹ It was found that meleagrin B (2) stimulated cell apoptosis of HL-60 at 5 and 10 µM, while meleagrin A (1) arrested the cell cycle via the G2/M phase.⁹

Recently, in a study on the effect of meleagrin A (1) against pulmonary fibrosis caused by bleomycin in mice, it was found that meleagrin A (1) has a protective effect.¹¹ Its effectiveness could be attributable to restoring the oxidant–antioxidant balance through reducing MDA contents and elevating the activities and levels of antioxidant molecules.¹¹

Conclusion

Meleagrins are bioactive fungal secondary metabolites mainly isolated from Penicillium species. The active components of these species were examined in order to get a deeper understanding of the biosynthetic processes and structure–activity connections in this family of metabolites, which resulted in the isolation of meleagrins. The gene cluster encoding for meleagrin production is a unique pathway in the biosynthesis of these compounds. The gene cluster encoding the production of meleagrins was identified using whole genome sequencing, analysis, and substrate modeling with P. chrysogenum. Through genetic studies within the roquefortin/meleagrin gene cluster in the P. chrysogenum genome, besides RNA silencing experiments, it has been confirmed that there is a putative biochemical mapping for each step of the biosynthetic pathway to reach the production of meleagrins. It can be confirmed by previous biological studies that meleagrin A is a unique alkaloid with promising biological properties, especially its ability to inhibit microbes, including Gram-positive and Gram-negative bacteria. On the other hand, it has the potential to be an anti-cancer agent. Additionally, in a distinct study, its ability to be an anti-fouling agent was demonstrated by a life cycle study of A. amphiplanus as a marine fouling agent without affecting its life cycle. This suggests that meleagrin A has no toxic effect.

Footnotes

Author Contributions

Eslam R. El-Sawy and Gilbert Kirsch: contributed to the conception of the study, collected literature, and revised it critically; Eslam R. El-Sawy: evaluated the literature and wrote the initial draft; Mohamed S. Abdel-Aziz: helped perform the analysis with constructive discussions; and Eslam R. El-Sawy, Mohamed S. Abdel-Aziz, and Gilbert Kirsch: contributed to writing the final draft and corrected the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Eslam R. El-Sawy

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A Literature Review of Meleagrins