Marine Drugs

66 pages, 7625 KiB

Open AccessEditor’s ChoiceReview

Advanced Methods for Natural Products Discovery: Bioactivity Screening, Dereplication, Metabolomics Profiling, Genomic Sequencing, Databases and Informatic Tools, and Structure Elucidation

by Susana P. Gaudêncio, Engin Bayram, Lada Lukić Bilela, Mercedes Cueto, Ana R. Díaz-Marrero, Berat Z. Haznedaroglu, Carlos Jimenez, Manolis Mandalakis, Florbela Pereira, Fernando Reyes and Deniz Tasdemir

Mar. Drugs 2023, 21(5), 308; https://doi.org/10.3390/md21050308 - 19 May 2023

Cited by 34 | Viewed by 13436

Abstract

Natural Products (NP) are essential for the discovery of novel drugs and products for numerous biotechnological applications. The NP discovery process is expensive and time-consuming, having as major hurdles dereplication (early identification of known compounds) and structure elucidation, particularly the determination of the [...] Read more.

Natural Products (NP) are essential for the discovery of novel drugs and products for numerous biotechnological applications. The NP discovery process is expensive and time-consuming, having as major hurdles dereplication (early identification of known compounds) and structure elucidation, particularly the determination of the absolute configuration of metabolites with stereogenic centers. This review comprehensively focuses on recent technological and instrumental advances, highlighting the development of methods that alleviate these obstacles, paving the way for accelerating NP discovery towards biotechnological applications. Herein, we emphasize the most innovative high-throughput tools and methods for advancing bioactivity screening, NP chemical analysis, dereplication, metabolite profiling, metabolomics, genome sequencing and/or genomics approaches, databases, bioinformatics, chemoinformatics, and three-dimensional NP structure elucidation. Full article

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14 pages, 1600 KiB

Open AccessEditor’s ChoiceArticle

Isolation of Nocuolin A and Synthesis of New Oxadiazine Derivatives. Design, Synthesis, Molecular Docking, Apoptotic Evaluation, and Cathepsin B Inhibition

by Víctor Tena Pérez, Luis Apaza Ticona, Alfredo H. Cabanillas, Santiago Maderuelo Corral, Diego Fernando Rosero Valencia, Antera Martel Quintana, Montserrat Ortega Domenech and Ángel Rumbero Sánchez

Mar. Drugs 2023, 21(5), 284; https://doi.org/10.3390/md21050284 - 29 Apr 2023

Cited by 2 | Viewed by 1728

Abstract

Nocuolin A (1), an oxadiazine, was isolated from the cyanobacterium Nostoc sp. Its chemical structure was elucidated using NMR and mass spectroscopic data. From this compound, two new oxadiazines, 3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropyl acetate (2) and 4-{3-[(6R [...] Read more.

Nocuolin A (1), an oxadiazine, was isolated from the cyanobacterium Nostoc sp. Its chemical structure was elucidated using NMR and mass spectroscopic data. From this compound, two new oxadiazines, 3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropyl acetate (2) and 4-{3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropoxy}-4-oxobutanoic acid (3), were synthesised. The chemical structures of these two compounds were elucidated by a combination of NMR and MS analysis. Compound 3 showed cytotoxicity against the ACHN (0.73 ± 0.10 μM) and Hepa-1c1c7 (0.91 ± 0.08 μM) tumour cell lines. Similarly, compound 3 significantly decreased cathepsin B activity in ACHN and Hepa-1c1c7 tumour cell lines at concentrations of 1.52 ± 0.13 nM and 1.76 ± 0.24 nM, respectively. In addition, compound 3 showed no in vivo toxicity in a murine model treated with a dose of 4 mg/kg body weight. Full article

(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)

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15 pages, 1883 KiB

Open AccessEditor’s ChoiceArticle

Enhanced Molecular Networking Shows Microbacterium sp. V1 as a Factory of Antioxidant Proline-Rich Peptides

by Giovanni Andrea Vitale, Silvia Scarpato, Alfonso Mangoni, Maria Valeria D’Auria, Gerardo Della Sala and Donatella de Pascale

Mar. Drugs 2023, 21(4), 256; https://doi.org/10.3390/md21040256 - 21 Apr 2023

Cited by 4 | Viewed by 3383

Abstract

Two linear proline-rich peptides (1–2), bearing an N-terminal pyroglutamate, were isolated from the marine bacterium Microbacterium sp. V1, associated with the marine sponge Petrosia ficiformis, collected in the volcanic CO₂ vents in Ischia Island (South Italy). Peptide [...] Read more.

Two linear proline-rich peptides (1–2), bearing an N-terminal pyroglutamate, were isolated from the marine bacterium Microbacterium sp. V1, associated with the marine sponge Petrosia ficiformis, collected in the volcanic CO₂ vents in Ischia Island (South Italy). Peptide production was triggered at low temperature following the one strain many compounds (OSMAC) method. Both peptides were detected together with other peptides (3–8) via an integrated, untargeted MS/MS-based molecular networking and cheminformatic approach. The planar structure of the peptides was determined by extensive 1D and 2D NMR and HR-MS analysis, and the stereochemistry of the aminoacyl residues was inferred by Marfey’s analysis. Peptides 1–8 are likely to arise from Microbacterium V1 tailor-made proteolysis of tryptone. Peptides 1 and 2 were shown to display antioxidant properties in the ferric-reducing antioxidant power (FRAP) assay. Full article

(This article belongs to the Section Marine Biotechnology Related to Drug Discovery or Production)

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18 pages, 2603 KiB

Open AccessEditor’s ChoiceArticle

Challenging Structure Elucidation of Lumnitzeralactone, an Ellagic Acid Derivative from the Mangrove Lumnitzera racemosa

by Jonas Kappen, Jeprianto Manurung, Tristan Fuchs, Sahithya Phani Babu Vemulapalli, Lea M. Schmitz, Andrej Frolov, Andria Agusta, Alexandra N. Muellner-Riehl, Christian Griesinger, Katrin Franke and Ludger A. Wessjohann

Mar. Drugs 2023, 21(4), 242; https://doi.org/10.3390/md21040242 - 14 Apr 2023

Viewed by 4383

Abstract

The previously undescribed natural product lumnitzeralactone (1), which represents a derivative of ellagic acid, was isolated from the anti-bacterial extract of the Indonesian mangrove species Lumnitzera racemosa Willd. The structure of lumnitzeralactone (1), a proton-deficient and highly challenging condensed [...] Read more.

The previously undescribed natural product lumnitzeralactone (1), which represents a derivative of ellagic acid, was isolated from the anti-bacterial extract of the Indonesian mangrove species Lumnitzera racemosa Willd. The structure of lumnitzeralactone (1), a proton-deficient and highly challenging condensed aromatic ring system, was unambiguously elucidated by extensive spectroscopic analyses involving high-resolution mass spectrometry (HRMS), 1D ¹H and ¹³C nuclear magnetic resonance spectroscopy (NMR), and 2D NMR (including 1,1-ADEQUATE and 1,n-ADEQUATE). Determination of the structure was supported by computer-assisted structure elucidation (CASE system applying ACD-SE), density functional theory (DFT) calculations, and a two-step chemical synthesis. Possible biosynthetic pathways involving mangrove-associated fungi have been suggested. Full article

(This article belongs to the Section Structural Studies on Marine Natural Products)

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32 pages, 761 KiB

Open AccessEditor’s ChoiceReview

Applications of Antioxidant Secondary Metabolites of Sargassum spp.

by Marcelo D. Catarino, Rita Silva-Reis, Amina Chouh, Sónia Silva, Susana S. Braga, Artur M. S. Silva and Susana M. Cardoso

Mar. Drugs 2023, 21(3), 172; https://doi.org/10.3390/md21030172 - 9 Mar 2023

Cited by 13 | Viewed by 7711

Abstract

Sargassum is one of the largest and most diverse genus of brown seaweeds, comprising of around 400 taxonomically accepted species. Many species of this genus have long been a part of human culture with applications as food, feed, and remedies in folk medicine. [...] Read more.

Sargassum is one of the largest and most diverse genus of brown seaweeds, comprising of around 400 taxonomically accepted species. Many species of this genus have long been a part of human culture with applications as food, feed, and remedies in folk medicine. Apart from their high nutritional value, these seaweeds are also a well-known reservoir of natural antioxidant compounds of great interest, including polyphenols, carotenoids, meroterpenoids, phytosterols, and several others. Such compounds provide a valuable contribution to innovation that can translate, for instance, into the development of new ingredients for preventing product deterioration, particularly in food products, cosmetics or biostimulants to boost crops production and tolerance to abiotic stress. This manuscript revises the chemical composition of Sargassum seaweeds, highlighting their antioxidant secondary metabolites, their mechanism of action, and multiple applications in fields, including agriculture, food, and health. Full article

(This article belongs to the Special Issue Seaweed Bioactive Metabolites: Health Benefits and Potential Applications)

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18 pages, 4780 KiB

Open AccessEditor’s ChoiceArticle

Marinobazzanan, a Bazzanane-Type Sesquiterpenoid, Suppresses the Cell Motility and Tumorigenesis in Cancer Cells

by Sultan Pulat, Prima F. Hillman, Sojeong Kim, Ratnakar N. Asolkar, Haerin Kim, Rui Zhou, İsa Taş, Chathurika D. B. Gamage, Mücahit Varlı, So-Yeon Park, Sung Chul Park, Inho Yang, Jongheon Shin, Dong-Chan Oh, Hangun Kim, Sang-Jip Nam and William Fenical

Mar. Drugs 2023, 21(3), 153; https://doi.org/10.3390/md21030153 - 25 Feb 2023

Cited by 6 | Viewed by 2872

Abstract

Marinobazzanan (1), a new bazzanane-type sesquiterpenoid, was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was elucidated using NMR and mass spectroscopic data, while the relative configurations were established through the analysis of [...] Read more.

Marinobazzanan (1), a new bazzanane-type sesquiterpenoid, was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was elucidated using NMR and mass spectroscopic data, while the relative configurations were established through the analysis of NOESY data. The absolute configurations of 1 were determined by the modified Mosher’s method as well as vibrational circular dichroism (VCD) spectra calculation and it was determined as 6R, 7R, 9R, and 10R. It was found that compound 1 was not cytotoxic to human cancer cells, including A549 (lung cancer), AGS (gastric cancer), and Caco-2 (colorectal cancer) below the concentration of 25 μM. However, compound 1 was shown to significantly decrease cancer-cell migration and invasion and soft-agar colony-formation ability at concentrations ranging from 1 to 5 μM by downregulating the expression level of KITENIN and upregulating the expression level of KAI1. Compound 1 suppressed β-catenin-mediated TOPFLASH activity and its downstream targets in AGS, A549, and Caco-2 and slightly suppressed the Notch signal pathway in three cancer cells. Furthermore, 1 also reduced the number of metastatic nodules in an intraperitoneal xenograft mouse model. Full article

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18 pages, 2608 KiB

Open AccessEditor’s ChoiceArticle

Bioactive Oxylipins Profile in Marine Microalgae

by Amandyne Linares-Maurizi, Guillaume Reversat, Rana Awad, Valérie Bultel-Poncé, Camille Oger, Jean-Marie Galano, Laurence Balas, Anaelle Durbec, Justine Bertrand-Michel, Thierry Durand, Rémi Pradelles and Claire Vigor

Mar. Drugs 2023, 21(3), 136; https://doi.org/10.3390/md21030136 - 22 Feb 2023

Cited by 10 | Viewed by 5874

Abstract

Microalgae are photosynthetic microscopic organisms that serve as the primary food source in aquatic environments. Microalgae can synthesize a wide variety of molecules, such as polyunsaturated fatty acids (PUFAs) of the omega-3 and omega-6 series. Oxidative degradation of PUFA due to radical and/or [...] Read more.

Microalgae are photosynthetic microscopic organisms that serve as the primary food source in aquatic environments. Microalgae can synthesize a wide variety of molecules, such as polyunsaturated fatty acids (PUFAs) of the omega-3 and omega-6 series. Oxidative degradation of PUFA due to radical and/or enzymatic conversion leads to the formation of oxylipins, which are compounds known for their bioactive properties. In the present study, we aim to profile oxylipins from five microalgae species grown in 10-L photo-bioreactors under optimal conditions. During their exponential phase, microalgae were harvested, extracted and analyzed by LC-MS/MS to determine the qualitative and quantitative profile of oxylipins for each species. The five different selected microalgae revealed a high diversity of metabolites, up to 33 non-enzymatic and 24 enzymatic oxylipins present in different concentrations. Taken together, these findings highlight an interesting role of marine microalgae as a source of bioactive lipids mediators, which we hypothesize have an important function in preventive health measures such as amelioration of inflammation. The rich mixture of oxylipins may display advantages to biological organisms, especially by providing for human health benefits including antioxidant, anti-inflammatory, neuroprotective or immunomodulator activities. Some oxylipins are also well known for their cardiovascular properties. Full article

(This article belongs to the Special Issue Marine-Derived Compounds Applied in Cardiovascular Disease)

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21 pages, 4498 KiB

Open AccessEditor’s ChoiceReview

Marine Organisms as a Prolific Source of Bioactive Depsipeptides

by Mingyuan Zeng, Jianyun Tao, Shuang Xu, Xuelian Bai and Huawei Zhang

Mar. Drugs 2023, 21(2), 120; https://doi.org/10.3390/md21020120 - 11 Feb 2023

Cited by 14 | Viewed by 2526

Abstract

Depsipeptides, an important group of polypeptides containing residues of hydroxy acids and amino acids linked together by amide and ester bonds, have potential applications in agriculture and medicine. A growing body of evidence demonstrates that marine organisms are prolific sources of depsipeptides, such [...] Read more.

Depsipeptides, an important group of polypeptides containing residues of hydroxy acids and amino acids linked together by amide and ester bonds, have potential applications in agriculture and medicine. A growing body of evidence demonstrates that marine organisms are prolific sources of depsipeptides, such as marine cyanobacteria, sponges, mollusks, microorganisms and algae. However, these substances have not yet been comprehensively summarized. In order to enrich our knowledge about marine depsipeptides, their biological sources and structural features, as well as bioactivities, are highlighted in this review after an extensive literature search and data analysis. Full article

(This article belongs to the Special Issue Marine Bioactive Peptides: Structure, Function, and Therapeutic Potential IV)

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13 pages, 562 KiB

Open AccessEditor’s ChoiceArticle

New Nostocyclophanes from Nostoc linckia

by Jingqiu Dai, Casey S. Philbin, Clay Wakano, Wesley Y. Yoshida and Philip G. Williams

Mar. Drugs 2023, 21(2), 101; https://doi.org/10.3390/md21020101 - 31 Jan 2023

Cited by 5 | Viewed by 4483

Abstract

Six new nostocyclophanes and four known compounds have been isolated from Nostoc linckia (Nostocaceae) cyanobacterial strain UTEX B1932. The new compounds, nostocyclophanes E–J (1–6), were characterized by NMR and MS techniques. The known compounds were nostocyclophanes B–D, previously isolated [...] Read more.

Six new nostocyclophanes and four known compounds have been isolated from Nostoc linckia (Nostocaceae) cyanobacterial strain UTEX B1932. The new compounds, nostocyclophanes E–J (1–6), were characterized by NMR and MS techniques. The known compounds were nostocyclophanes B–D, previously isolated from this strain, and dedichloronostocyclophane D. Structural modifications on the new [7.7]paracyclophane analogs 1–5, isolated from the 80% methanol fraction, range from simple changes such as the lack of methylation or halogenation to more unusual modifications such as those seen in nostocyclophane H (4), in which the exocyclic alkyl chains are of different length; this is the first time this modification has been observed in this family of natural products. In addition, nostocyclophane J (6) is a linear analog in which C-20 is chlorinated in preparation for the presumed enzymatic Friedel–Craft cyclization needed to form the final ring structure, analogous to the biosynthesis of the related cylindrocyclophanes. Nostocyclophane D, dedichloronostocyclophane D, and nostocyclophanes E-J demonstrated moderate to weak growth inhibition against MDA-MB-231 breast cancer cells. Full article

(This article belongs to the Special Issue Bioactive Products from Marine Cyanobacteria and Their Potential Therapeutic Applications 2022)

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15 pages, 3925 KiB

Open AccessEditor’s ChoiceReview

Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)

by Enrico D’Aniello, Pietro Amodeo and Rosa Maria Vitale

Mar. Drugs 2023, 21(2), 89; https://doi.org/10.3390/md21020089 - 26 Jan 2023

Cited by 8 | Viewed by 3871

Abstract

Peroxisome proliferator-activated receptors α, γ and β/δ (PPARα, PPARγ, and PPARβ/δ) are a family of ligand-activated transcriptional factors belonging to the superfamily of nuclear receptors regulating the expression of genes involved in lipid and carbohydrate metabolism, energy homeostasis, inflammation, and the immune response. [...] Read more.

Peroxisome proliferator-activated receptors α, γ and β/δ (PPARα, PPARγ, and PPARβ/δ) are a family of ligand-activated transcriptional factors belonging to the superfamily of nuclear receptors regulating the expression of genes involved in lipid and carbohydrate metabolism, energy homeostasis, inflammation, and the immune response. For this reason, they represent attractive targets for the treatment of a variety of metabolic diseases and, more recently, for neurodegenerative disorders due to their emerging neuroprotective effects. The degree of activation, from partial to full, along with the selectivity toward the different isoforms, greatly affect the therapeutic efficacy and the safety profile of PPAR agonists. Thus, there is a high interest toward novel scaffolds with proper combinations of activity and selectivity. This review intends to provide an overview of the discovery, optimization, and structure–activity relationship studies on PPAR modulators from marine sources, along with the structural and computational studies that led to their identification and/or elucidation, and rationalization of their mechanisms of action. Full article

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30 pages, 2013 KiB

Open AccessEditor’s ChoiceReview

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

by Mingyue Zhang, Qinrong Zhang, Qunde Zhang, Xinyuan Cui and Lifeng Zhu

Mar. Drugs 2023, 21(2), 84; https://doi.org/10.3390/md21020084 - 25 Jan 2023

Cited by 4 | Viewed by 3293

Abstract

Parasitic diseases still threaten human health. At present, a number of parasites have developed drug resistance, and it is urgent to find new and effective antiparasitic drugs. As a rich source of biological compounds, marine natural products have been increasingly screened as candidates [...] Read more.

Parasitic diseases still threaten human health. At present, a number of parasites have developed drug resistance, and it is urgent to find new and effective antiparasitic drugs. As a rich source of biological compounds, marine natural products have been increasingly screened as candidates for developing new antiparasitic drugs. The literature related to the study of the antigenic animal activity of marine natural compounds from invertebrates and microorganisms was selected to summarize the research progress of marine compounds and the structure–activity relationship of these compounds in the past five years and to explore the possible sources of potential antiparasitic drugs for parasite treatment. Full article

(This article belongs to the Special Issue Marine Antiparasitic Agents)

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15 pages, 2339 KiB

Open AccessEditor’s ChoiceArticle

Secondary Metabolites with Anti-Inflammatory Activity from Laurencia majuscula Collected in the Red Sea

by Mohamed A. Tammam, Maria G. Daskalaki, Nikolaos Tsoureas, Ourania Kolliniati, Aldoushy Mahdy, Sotirios C. Kampranis, Christos Tsatsanis, Vassilios Roussis and Efstathia Ioannou

Mar. Drugs 2023, 21(2), 79; https://doi.org/10.3390/md21020079 - 24 Jan 2023

Cited by 5 | Viewed by 4392

Abstract

The chemical investigation of the organic extract of the red alga Laurencia majuscula collected from Hurghada reef in the Red Sea resulted in the isolation of five C₁₅ acetogenins, including four tricyclic ones of the maneonene type (1–4) [...] Read more.

The chemical investigation of the organic extract of the red alga Laurencia majuscula collected from Hurghada reef in the Red Sea resulted in the isolation of five C₁₅ acetogenins, including four tricyclic ones of the maneonene type (1–4) and a 5-membered one (5), 15 sesquiterpenes, including seven lauranes (6–12), one cuparane (13), one seco-laurane (14), one snyderane (15), two chamigranes (16, 17), two rearranged chamigranes (18, 19) and one aristolane (20), as well as a tricyclic diterpene (21) and a chlorinated fatty acid derivative (22). Among them, compounds 1–3, 5, 7, 8, 10, 11 and 14 are new natural products. The structures and the relative configurations of the isolated natural products have been established based on extensive analysis of their NMR and MS data, while the absolute configuration of maneonenes F (1) and G (2) was determined on the basis of single-crystal X-ray diffraction analysis. The anti-inflammatory activity of compounds 1, 2, 4–8, 10, 12–16, 18 and 20–22 was evaluated by measuring suppression of nitric oxide (NO) release in TLR4-activated RAW 264.7 macrophages in culture. All compounds, except 6, exhibited significant anti-inflammatory activity. Among them, metabolites 1, 4 and 18 did not exhibit any cytostatic activity at the tested concentrations. The most prominent anti-inflammatory activity, accompanied by absence of cytostatic activity at the same concentration, was exerted by compounds 5 and 18, with IC₅₀ values of 3.69 μM and 3.55 μΜ, respectively. Full article

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18 pages, 2998 KiB

Open AccessEditor’s ChoiceArticle

Cryptic Diversity of Black Band Disease Cyanobacteria in Siderastrea siderea Corals Revealed by Chemical Ecology and Comparative Genome-Resolved Metagenomics

by Julie L. Meyer, Sarath P. Gunasekera, Anya L. Brown, Yousong Ding, Stephanie Miller, Max Teplitski and Valerie J. Paul

Mar. Drugs 2023, 21(2), 76; https://doi.org/10.3390/md21020076 - 22 Jan 2023

Cited by 7 | Viewed by 4849

Abstract

Black band disease is a globally distributed and easily recognizable coral disease. Despite years of study, the etiology of this coral disease, which impacts dozens of stony coral species, is not completely understood. Although black band disease mats are predominantly composed of the [...] Read more.

Black band disease is a globally distributed and easily recognizable coral disease. Despite years of study, the etiology of this coral disease, which impacts dozens of stony coral species, is not completely understood. Although black band disease mats are predominantly composed of the cyanobacterial species Roseofilum reptotaenium, other filamentous cyanobacterial strains and bacterial heterotrophs are readily detected. Through chemical ecology and metagenomic sequencing, we uncovered cryptic strains of Roseofilum species from Siderastrea siderea corals that differ from those on other corals in the Caribbean and Pacific. Isolation of metabolites from Siderastrea-derived Roseofilum revealed the prevalence of unique forms of looekeyolides, distinct from previously characterized Roseofilum reptotaenium strains. In addition, comparative genomics of Roseofilum strains showed that only Siderastrea-based Roseofilum strains have the genetic capacity to produce lasso peptides, a family of compounds with diverse biological activity. All nine Roseofilum strains examined here shared the genetic capacity to produce looekeyolides and malyngamides, suggesting these compounds support the ecology of this genus. Similar biosynthetic gene clusters are not found in other cyanobacterial genera associated with black band disease, which may suggest that looekeyolides and malyngamides contribute to disease etiology through yet unknown mechanisms. Full article

(This article belongs to the Special Issue Reef Ecology and Marine Drug Discovery)

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19 pages, 17326 KiB

Open AccessEditor’s ChoiceArticle

Botryllin, a Novel Antimicrobial Peptide from the Colonial Ascidian Botryllus schlosseri

by Nicola Franchi, Loriano Ballarin and Francesca Cima

Mar. Drugs 2023, 21(2), 74; https://doi.org/10.3390/md21020074 - 21 Jan 2023

Cited by 6 | Viewed by 3479

Abstract

By mining the transcriptome of the colonial ascidian Botryllus schlosseri, we identified a transcript for a novel styelin-like antimicrobial peptide, which we named botryllin. The gene is constitutively transcribed by circulating cytotoxic morula cells (MCs) as a pre-propeptide that is then cleaved [...] Read more.

By mining the transcriptome of the colonial ascidian Botryllus schlosseri, we identified a transcript for a novel styelin-like antimicrobial peptide, which we named botryllin. The gene is constitutively transcribed by circulating cytotoxic morula cells (MCs) as a pre-propeptide that is then cleaved to mature peptide. The synthetic peptide, obtained from in silico translation of the transcript, shows robust killing activity of bacterial and unicellular yeast cells, causing breakages of both the plasma membrane and the cell wall. Specific monoclonal antibodies were raised against the epitopes of the putative amino acid sequence of the propeptide and the mature peptide; in both cases, they label the MC granular content. Upon MC degranulation induced by the presence of nonself, the antibodies recognise the extracellular nets with entrapped bacteria nearby MC remains. The obtained results suggest that the botryllin gene carries the information for the synthesis of an AMP involved in the protection of B. schlosseri from invading foreign cells. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products)

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14 pages, 3607 KiB

Open AccessEditor’s ChoiceArticle

Molecular Networking Revealed Unique UV-Absorbing Phospholipids: Favilipids from the Marine Sponge Clathria faviformis

by Silvia Scarpato, Roberta Teta, Paola De Cicco, Francesca Borrelli, Joseph R. Pawlik, Valeria Costantino and Alfonso Mangoni

Mar. Drugs 2023, 21(2), 58; https://doi.org/10.3390/md21020058 - 18 Jan 2023

Cited by 2 | Viewed by 3315

Abstract

Analysis of extracts of the marine sponge Clathria faviformis by high-resolution LC-MS² and molecular networking resulted in the discovery of a new family of potentially UV-protecting phospholipids, the favilipids. One of them, favilipid A (1), was isolated and its structure [...] Read more.

Analysis of extracts of the marine sponge Clathria faviformis by high-resolution LC-MS² and molecular networking resulted in the discovery of a new family of potentially UV-protecting phospholipids, the favilipids. One of them, favilipid A (1), was isolated and its structure determined by mass and tandem mass spectrometry, NMR, electronic circular dichroism (ECD), and computational studies. Favilipid A, which has no close analogues among natural products, possesses an unprecedented structure characterized by a 4-aminodihydropiridinium core, resulting in UV-absorbing properties that are very unusual for a phospholipid. Consequently, favilipid A could inspire the development of a new class of molecules to be used as sunscreen ingredients. In addition, favilipid A inhibited by 58–48% three kinases (JAK3, IKKβ, and SYK) involved in the regulation of the immune system, suggesting a potential use for treatment of autoimmune diseases, hematologic cancers, and other inflammatory states. Full article

(This article belongs to the Special Issue Discovering Marine Bioactive Compounds by Molecular Networking)

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26 pages, 2681 KiB

Open AccessEditor’s ChoiceReview

Secondary Metabolites from Marine-Derived Bacteria with Antibiotic and Antibiofilm Activities against Drug-Resistant Pathogens

by Joko Tri Wibowo, Asep Bayu, Widya Dwi Aryati, Carla Fernandes, Arry Yanuar, Anake Kijjoa and Masteria Yunovilsa Putra

Mar. Drugs 2023, 21(1), 50; https://doi.org/10.3390/md21010050 - 12 Jan 2023

Cited by 17 | Viewed by 5550

Abstract

The search for new antibiotics against drug-resistant microbes has been expanded to marine bacteria. Marine bacteria have been proven to be a prolific source of a myriad of novel compounds with potential biological activities. Therefore, this review highlights novel and bioactive compounds from [...] Read more.

The search for new antibiotics against drug-resistant microbes has been expanded to marine bacteria. Marine bacteria have been proven to be a prolific source of a myriad of novel compounds with potential biological activities. Therefore, this review highlights novel and bioactive compounds from marine bacteria reported during the period of January 2016 to December 2021. Published articles containing novel marine bacterial secondary metabolites that are active against drug-resistant pathogens were collected. Previously described compounds (prior to January 2016) are not included in this review. Unreported compounds during this period that exhibited activity against pathogenic microbes were discussed and compared in order to find the cue of the structure–bioactivity relationship. The results showed that Streptomyces are the most studied bacteria with undescribed bioactive compounds, followed by other genera in the Actinobacteria. We have categorized the structures of the compounds in the present review into four groups, based on their biosynthetic origins, as polyketide derivatives, amino acid derivatives, terpenoids, as well as compounds with mixed origin. These compounds were active against one or more drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin-resistant Enterococci (VRE), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and amphotericin B-resistant Candida albicans. In addition, some of the compounds also showed activity against biofilm formation of the test bacteria. Some previously undescribed compounds, isolated from marine-derived bacteria during this period, could have a good potential as lead compounds for the development of drug candidates to overcome multidrug-resistant pathogens. Full article

(This article belongs to the Special Issue Pharmaceutical, Nutraceutical, Cosmeceutical and Biotechnological Potentials of Southeast Asian Marine Resources)

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28 pages, 6086 KiB

Open AccessEditor’s ChoiceArticle

Marine Sponge and Octocoral-Associated Bacteria Show Versatile Secondary Metabolite Biosynthesis Potential and Antimicrobial Activities against Human Pathogens

by João F. Almeida, Matilde Marques, Vanessa Oliveira, Conceição Egas, Dalila Mil-Homens, Romeu Viana, Daniel F. R. Cleary, Yusheng M. Huang, Arsénio M. Fialho, Miguel C. Teixeira, Newton C. M. Gomes, Rodrigo Costa and Tina Keller-Costa

Mar. Drugs 2023, 21(1), 34; https://doi.org/10.3390/md21010034 - 30 Dec 2022

Cited by 7 | Viewed by 5356

Abstract

Marine microbiomes are prolific sources of bioactive natural products of potential pharmaceutical value. This study inspected two culture collections comprising 919 host-associated marine bacteria belonging to 55 genera and several thus-far unclassified lineages to identify isolates with potentially rich secondary metabolism and antimicrobial [...] Read more.

Marine microbiomes are prolific sources of bioactive natural products of potential pharmaceutical value. This study inspected two culture collections comprising 919 host-associated marine bacteria belonging to 55 genera and several thus-far unclassified lineages to identify isolates with potentially rich secondary metabolism and antimicrobial activities. Seventy representative isolates had their genomes mined for secondary metabolite biosynthetic gene clusters (SM-BGCs) and were screened for antimicrobial activities against four pathogenic bacteria and five pathogenic Candida strains. In total, 466 SM-BGCs were identified, with antimicrobial peptide- and polyketide synthase-related SM-BGCs being frequently detected. Only 38 SM-BGCs had similarities greater than 70% to SM-BGCs encoding known compounds, highlighting the potential biosynthetic novelty encoded by these genomes. Cross-streak assays showed that 33 of the 70 genome-sequenced isolates were active against at least one Candida species, while 44 isolates showed activity against at least one bacterial pathogen. Taxon-specific differences in antimicrobial activity among isolates suggested distinct molecules involved in antagonism against bacterial versus Candida pathogens. The here reported culture collections and genome-sequenced isolates constitute a valuable resource of understudied marine bacteria displaying antimicrobial activities and potential for the biosynthesis of novel secondary metabolites, holding promise for a future sustainable production of marine drug leads. Full article

(This article belongs to the Special Issue Reef Ecology and Marine Drug Discovery)

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26 pages, 5346 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Recent Advancement in Anticancer Compounds from Marine Organisms: Approval, Use and Bioinformatic Approaches to Predict New Targets

by Giovanna Santaniello, Angela Nebbioso, Lucia Altucci and Mariarosaria Conte

Mar. Drugs 2023, 21(1), 24; https://doi.org/10.3390/md21010024 - 28 Dec 2022

Cited by 6 | Viewed by 4936

Abstract

In recent years, the study of anticancer bioactive compounds from marine sources has received wide interest. Contextually, world regulatory authorities have approved several marine molecules, and new synthetic derivatives have also been synthesized and structurally improved for the treatment of numerous forms of [...] Read more.

In recent years, the study of anticancer bioactive compounds from marine sources has received wide interest. Contextually, world regulatory authorities have approved several marine molecules, and new synthetic derivatives have also been synthesized and structurally improved for the treatment of numerous forms of cancer. However, the administration of drugs in cancer patients requires careful evaluation since their interaction with individual biological macromolecules, such as proteins or nucleic acids, determines variable downstream effects. This is reflected in a constant search for personalized therapies that lay the foundations of modern medicine. The new knowledge acquired on cancer mechanisms has certainly allowed advancements in tumor prevention, but unfortunately, due to the huge complexity and heterogeneity of cancer, we are still looking for a definitive therapy and clinical approaches. In this review, we discuss the significance of recently approved molecules originating from the marine environment, starting from their organism of origin to their structure and mechanism of action. Subsequently, these bio-compounds are used as models to illustrate possible bioinformatics approaches for the search of new targets that are useful for improving the knowledge on anticancer therapies. Full article

(This article belongs to the Special Issue Bioinformatics of Marine Natural Products 2.0)

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17 pages, 641 KiB

Open AccessEditor’s ChoiceArticle

Never, Ever Make an Enemy… Out of an Anemone: Transcriptomic Comparison of Clownfish Hosting Sea Anemone Venoms

by Alonso Delgado, Charlotte Benedict, Jason Macrander and Marymegan Daly

Mar. Drugs 2022, 20(12), 730; https://doi.org/10.3390/md20120730 - 23 Nov 2022

Cited by 10 | Viewed by 4784

Abstract

Sea anemones are predatory marine invertebrates and have diverse venom arsenals. Venom is integral to their biology, and is used in competition, defense, and feeding. Three lineages of sea anemones are known to have independently evolved symbiotic relationships with clownfish, however the evolutionary [...] Read more.

Sea anemones are predatory marine invertebrates and have diverse venom arsenals. Venom is integral to their biology, and is used in competition, defense, and feeding. Three lineages of sea anemones are known to have independently evolved symbiotic relationships with clownfish, however the evolutionary impact of this relationship on the venom composition of the host is still unknown. Here, we investigate the potential of this symbiotic relationship to shape the venom profiles of the sea anemones that host clownfish. We use transcriptomic data to identify differences and similarities in venom profiles of six sea anemone species, representing the three known clades of clownfish-hosting sea anemones. We recovered 1121 transcripts matching verified toxins across all species, and show that hemolytic and hemorrhagic toxins are consistently the most dominant and diverse toxins across all species examined. These results are consistent with the known biology of sea anemones, provide foundational data on venom diversity of these species, and allow for a review of existing hierarchical structures in venomic studies. Full article

(This article belongs to the Special Issue Anthozoan Toxins: Using New Approaches to Understand Their Composition, Distribution, and Function)

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22 pages, 2920 KiB

Open AccessEditor’s ChoiceArticle

A Metabolomics-Based Toolbox to Assess and Compare the Metabolic Potential of Unexplored, Difficult-to-Grow Bacteria

by Federica Fiorini, Felizitas Bajerski, Olga Jeske, Cendrella Lepleux, Jörg Overmann and Mark Brönstrup

Mar. Drugs 2022, 20(11), 713; https://doi.org/10.3390/md20110713 - 14 Nov 2022

Cited by 4 | Viewed by 2794

Abstract

Novel high-throughput cultivation techniques create a demand to pre-select strains for in-depth follow-up studies. We report a workflow to identify promising producers of novel natural products by systematically characterizing their metabolomes. For this purpose, 60 strains from four phyla (Proteobacteria, Bacteroidetes, Actinobacteria and [...] Read more.

Novel high-throughput cultivation techniques create a demand to pre-select strains for in-depth follow-up studies. We report a workflow to identify promising producers of novel natural products by systematically characterizing their metabolomes. For this purpose, 60 strains from four phyla (Proteobacteria, Bacteroidetes, Actinobacteria and Firmicutes) comprising 16 novel species and six novel genera were cultivated from marine and terrestrial sources. Their cellular metabolomes were recorded by LC-MS/MS; data analysis comprised databases MS/MS matching, in silico compound assignment, and GNPS-based molecular networking. Overall, 1052 different molecules were identified from 6418 features, among them were unusual metabolites such as 4-methoxychalcone. Only a minor portion of the 755 features were found in all phyla, while the majority occurred in a single phylogroup or even in a single strain. Metabolomic methods enabled the recognition of highly talented strains such as AEG42_45, which had 107 unique features, among which a family of 28 potentially novel and related compounds according to MS/MS similarities. In summary, we propose that high-throughput cultivation and isolation of bacteria in combination with the presented systematic and unbiased metabolome analysis workflow is a promising approach to capture and assess the enormous metabolic potential of previously uncultured bacteria. Full article

(This article belongs to the Special Issue Marine Metabolomics 2023)

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13 pages, 1141 KiB

Open AccessEditor’s ChoiceArticle

Computational Metabolomics Tools Reveal Subarmigerides, Unprecedented Linear Peptides from the Marine Sponge Holobiont Callyspongia subarmigera

by Andrea Castaldi, Roberta Teta, Germana Esposito, Mehdi A. Beniddir, Nicole J. De Voogd, Sébastien Duperron, Valeria Costantino and Marie-Lise Bourguet-Kondracki

Mar. Drugs 2022, 20(11), 673; https://doi.org/10.3390/md20110673 - 27 Oct 2022

Cited by 3 | Viewed by 4306

Abstract

A detailed examination of a unique molecular family, restricted to the Callyspongia genus, in a molecular network obtained from an in-house Haplosclerida marine sponge collection (including Haliclona, Callyspongia, Xestospongia, and Petrosia species) led to the discovery of subarmigerides, a series [...] Read more.

A detailed examination of a unique molecular family, restricted to the Callyspongia genus, in a molecular network obtained from an in-house Haplosclerida marine sponge collection (including Haliclona, Callyspongia, Xestospongia, and Petrosia species) led to the discovery of subarmigerides, a series of rare linear peptides from Callyspongia subarmigera, a genus mainly known for polyacetylenes and lipids. The structure of the sole isolated peptide, subarmigeride A (1) was elucidated through extensive 1D and 2D NMR spectroscopy, HRMS/MS, and Marfey’s method to assign its absolute configuration. The putative structures of seven additional linear peptides were proposed by an analysis of their respective MS/MS spectra and a comparison of their fragmentation patterns with the heptapeptide 1. Surprisingly, several structurally related analogues of subarmigeride A (1) occurred in one distinct cluster from the molecular network of the cyanobacteria strains of the Guadeloupe mangroves, suggesting that the true producer of this peptide family might be the microbial sponge-associated community, i.e., the sponge-associated cyanobacteria. Full article

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32 pages, 9725 KiB

Open AccessEditor’s ChoiceReview

The Tetrahydrofuran Motif in Marine Lipids and Terpenes

by Paula González-Andrés, Laura Fernández-Peña, Carlos Díez-Poza and Asunción Barbero

Mar. Drugs 2022, 20(10), 642; https://doi.org/10.3390/md20100642 - 15 Oct 2022

Cited by 13 | Viewed by 3438

Abstract

Heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades. [...] Read more.

Heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades. They show promising biological activities, making them potential leads for novel antibiotics, antikinetoplastid drugs, amoebicidal substances, or anticancer drugs. Thus, they have attracted the attention of the synthetics community and numerous approaches to their total syntheses have appeared. Here, we offer the reader an overview of marine-derived terpenoids and related compounds, their isolation, structure determination, and a special focus on their total syntheses and biological profiles. Full article

(This article belongs to the Special Issue Heterocyclic Compounds from Marine Organisms)

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17 pages, 2576 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

An Aminopyrimidone and Aminoimidazoles Alkaloids from the Rodrigues Calcareous Marine Sponge Ernsta naturalis

by Pierre-Eric Campos, Gaëtan Herbette, Laetitia Fougère, Patricia Clerc, Florent Tintillier, Nicole J. de Voogd, Géraldine Le Goff, Jamal Ouazzani and Anne Gauvin-Bialecki

Mar. Drugs 2022, 20(10), 637; https://doi.org/10.3390/md20100637 - 13 Oct 2022

Cited by 3 | Viewed by 2624

Abstract

A chemical study of the CH₂Cl₂−MeOH (1:1) extract from the sponge Ernsta naturalis collected in Rodrigues (Mauritius) based on a molecular networking dereplication strategy highlighted one novel aminopyrimidone alkaloid compound, ernstine A (1), seven new aminoimidazole alkaloid [...] Read more.

A chemical study of the CH₂Cl₂−MeOH (1:1) extract from the sponge Ernsta naturalis collected in Rodrigues (Mauritius) based on a molecular networking dereplication strategy highlighted one novel aminopyrimidone alkaloid compound, ernstine A (1), seven new aminoimidazole alkaloid compounds, phorbatopsins D–E (2, 3), calcaridine C (4), naamines H–I (5, 7), naamidines J–K (6, 8), along with the known thymidine (9). Their structures were established by spectroscopic analysis (1D and 2D NMR spectra and HRESIMS data). To improve the investigation of this unstudied calcareous marine sponge, a metabolomic study by molecular networking was conducted. The isolated molecules are distributed in two clusters of interest. Naamine and naamidine derivatives are grouped together with ernstine in the first cluster of twenty-three molecules. Phorbatopsin derivatives and calcaridine C are grouped together in a cluster of twenty-one molecules. Interpretation of the MS/MS spectra of other compounds of these clusters with structural features close to the isolated ones allowed us to propose a structural hypothesis for 16 compounds, 5 known and 11 potentially new. Full article

(This article belongs to the Special Issue Heterocyclic Compounds from Marine Organisms)

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31 pages, 8660 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Targeted Isolation of Antibiotic Brominated Alkaloids from the Marine Sponge Pseudoceratina durissima Using Virtual Screening and Molecular Networking

by James Lever, Florian Kreuder, Jason Henry, Andrew Hung, Pierre-Marie Allard, Robert Brkljača, Colin Rix, Aya C. Taki, Robin B. Gasser, Jan Kaslin, Donald Wlodkowic, Jean-Luc Wolfender and Sylvia Urban

Mar. Drugs 2022, 20(9), 554; https://doi.org/10.3390/md20090554 - 29 Aug 2022

Cited by 5 | Viewed by 4457

Abstract

Many targeted natural product isolation approaches rely on the use of pre-existing bioactivity information to inform the strategy used for the isolation of new bioactive compounds. Bioactivity information can be available either in the form of prior assay data or via Structure Activity [...] Read more.

Many targeted natural product isolation approaches rely on the use of pre-existing bioactivity information to inform the strategy used for the isolation of new bioactive compounds. Bioactivity information can be available either in the form of prior assay data or via Structure Activity Relationship (SAR) information which can indicate a potential chemotype that exhibits a desired bioactivity. The work described herein utilizes a unique method of targeted isolation using structure-based virtual screening to identify potential antibacterial compounds active against MRSA within the marine sponge order Verongiida. This is coupled with molecular networking-guided, targeted isolation to provide a novel drug discovery procedure. A total of 12 previously reported bromotyrosine-derived alkaloids were isolated from the marine sponge species Pseudoceratina durissima, and the compound, (+)-aeroplysinin-1 (1) displayed activity against the MRSA pathogen (MIC: <32 µg/mL). The compounds (1–3, 6 and 9) were assessed for their central nervous system (CNS) interaction and behavioral toxicity to zebrafish (Danio rerio) larvae, whereby several of the compounds were shown to induce significant hyperactivity. Anthelmintic activity against the parasitic nematode Haemonchus contorutus was also evaluated (2–4, 6–8). Full article

(This article belongs to the Special Issue Discovering Marine Bioactive Compounds by Molecular Networking)

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18 pages, 3013 KiB

Open AccessEditor’s ChoiceReview

Marine Bacterial Ribosomal Peptides: Recent Genomics- and Synthetic Biology-Based Discoveries and Biosynthetic Studies

by Linda Sukmarini

Mar. Drugs 2022, 20(9), 544; https://doi.org/10.3390/md20090544 - 24 Aug 2022

Cited by 6 | Viewed by 3976

Abstract

Marine biodiversity is represented by an exceptional and ample array of intriguing natural product chemistries. Due to their extensive post-translational modifications, ribosomal peptides—also known as ribosomally synthesized and post-translationally modified peptides (RiPPs)—exemplify a widely diverse class of natural products, endowing a broad range [...] Read more.

Marine biodiversity is represented by an exceptional and ample array of intriguing natural product chemistries. Due to their extensive post-translational modifications, ribosomal peptides—also known as ribosomally synthesized and post-translationally modified peptides (RiPPs)—exemplify a widely diverse class of natural products, endowing a broad range of pharmaceutically and biotechnologically relevant properties for therapeutic or industrial applications. Most RiPPs are of bacterial origin, yet their marine derivatives have been quite rarely investigated. Given the rapid advancement engaged in a more powerful genomics approach, more biosynthetic gene clusters and pathways for these ribosomal peptides continue to be increasingly characterized. Moreover, the genome-mining approach in integration with synthetic biology techniques has markedly led to a revolution of RiPP natural product discovery. Therefore, this present short review article focuses on the recent discovery of RiPPs from marine bacteria based on genome mining and synthetic biology approaches during the past decade. Their biosynthetic studies are discussed herein, particularly the organization of targeted biosynthetic gene clusters linked to the encoded RiPPs with potential bioactivities. Full article

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69 pages, 21855 KiB

Open AccessEditor’s ChoiceReview

Anthraquinones and Their Analogues from Marine-Derived Fungi: Chemistry and Biological Activities

by Salar Hafez Ghoran, Fatemeh Taktaz, Seyed Abdulmajid Ayatollahi and Anake Kijjoa

Mar. Drugs 2022, 20(8), 474; https://doi.org/10.3390/md20080474 - 25 Jul 2022

Cited by 29 | Viewed by 5070

Abstract

Anthraquinones are an interesting chemical class of polyketides since they not only exhibit a myriad of biological activities but also contribute to managing ecological roles. In this review article, we provide a current knowledge on the anthraquinoids reported from marine-derived fungi, isolated from [...] Read more.

Anthraquinones are an interesting chemical class of polyketides since they not only exhibit a myriad of biological activities but also contribute to managing ecological roles. In this review article, we provide a current knowledge on the anthraquinoids reported from marine-derived fungi, isolated from various resources in both shallow waters such as mangrove plants and sediments of the mangrove habitat, coral reef, algae, sponges, and deep sea. This review also tentatively categorizes anthraquinone metabolites from the simplest to the most complicated scaffolds such as conjugated xanthone–anthraquinone derivatives and bianthraquinones, which have been isolated from marine-derived fungi, especially from the genera Apergillus, Penicillium, Eurotium, Altenaria, Fusarium, Stemphylium, Trichoderma, Acremonium, and other fungal strains. The present review, covering a range from 2000 to 2021, was elaborated through a comprehensive literature search using the following databases: ACS publications, Elsevier, Taylor and Francis, Wiley Online Library, MDPI, Springer, and Thieme. Thereupon, we have summarized and categorized 296 anthraquinones and their derivatives, some of which showed a variety of biological properties such as enzyme inhibition, antibacterial, antifungal, antiviral, antitubercular (against Mycobacterium tuberculosis), cytotoxic, anti-inflammatory, antifouling, and antioxidant activities. In addition, proposed biogenetic pathways of some anthraquinone derivatives are also discussed. Full article

(This article belongs to the Special Issue Pharmaceutical, Nutraceutical, Cosmeceutical and Biotechnological Potentials of Southeast Asian Marine Resources)

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20 pages, 2877 KiB

Open AccessEditor’s ChoiceArticle

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK

by Daphne R. Mattos, Xuemei Wan, Jeffrey D. Serrill, Minh H. Nguyen, Ian R. Humphreys, Benoit Viollet, Amos B. Smith III, Kerry L. McPhail and Jane E. Ishmael

Mar. Drugs 2022, 20(7), 418; https://doi.org/10.3390/md20070418 - 27 Jun 2022

Cited by 6 | Viewed by 3416

Abstract

The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with [...] Read more.

The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK. Full article

(This article belongs to the Special Issue Pharmacological Activity and Biomedical Potential of Marine Antitumor Agents)

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21 pages, 1375 KiB

Open AccessEditor’s ChoiceReview

Recent Discoveries on Marine Organism Immunomodulatory Activities

by Eleonora Montuori, Donatella de Pascale and Chiara Lauritano

Mar. Drugs 2022, 20(7), 422; https://doi.org/10.3390/md20070422 - 27 Jun 2022

Cited by 20 | Viewed by 5576

Abstract

Marine organisms have been shown to be a valuable source for biologically active compounds for the prevention and treatment of cancer, inflammation, immune system diseases, and other pathologies. The advantage of studying organisms collected in the marine environment lies in their great biodiversity [...] Read more.

Marine organisms have been shown to be a valuable source for biologically active compounds for the prevention and treatment of cancer, inflammation, immune system diseases, and other pathologies. The advantage of studying organisms collected in the marine environment lies in their great biodiversity and in the variety of chemical structures of marine natural products. Various studies have focused on marine organism compounds with potential pharmaceutical applications, for instance, as immunomodulators, to treat cancer and immune-mediated diseases. Modulation of the immune system is defined as any change in the immune response that can result in the induction, expression, amplification, or inhibition of any phase of the immune response. Studies very often focus on the effects of marine-derived compounds on macrophages, as well as lymphocytes, by analyzing the release of mediators (cytokines) by using the immunological assay enzyme-linked immunosorbent assay (ELISA), Western blot, immunofluorescence, and real-time PCR. The main sources are fungi, bacteria, microalgae, macroalgae, sponges, mollusks, corals, and fishes. This review is focused on the marine-derived molecules discovered in the last three years as potential immunomodulatory drugs. Full article

(This article belongs to the Section Marine Chemoecology for Drug Discovery)

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22 pages, 4580 KiB

Open AccessEditor’s ChoiceReview

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

by Cristina Porras-Alcalá, Federico Moya-Utrera, Miguel García-Castro, Antonio Sánchez-Ruiz, Juan Manuel López-Romero, María Soledad Pino-González, Amelia Díaz-Morilla, Seiya Kitamura, Dennis W. Wolan, José Prados, Consolación Melguizo, Iván Cheng-Sánchez and Francisco Sarabia

Mar. Drugs 2022, 20(6), 373; https://doi.org/10.3390/md20060373 - 31 May 2022

Cited by 9 | Viewed by 3917

Abstract

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total [...] Read more.

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry. Full article

(This article belongs to the Special Issue Marine Drugs Research in Spain)

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13 pages, 7390 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Preclinical Development of Seriniquinones as Selective Dermcidin Modulators for the Treatment of Melanoma

by Amanda S. Hirata, James J. La Clair, Paula C. Jimenez, Leticia Veras Costa-Lotufo and William Fenical

Mar. Drugs 2022, 20(5), 301; https://doi.org/10.3390/md20050301 - 28 Apr 2022

Cited by 3 | Viewed by 3525

Abstract

The bioactive natural product seriniquinone was discovered as a potential melanoma drug, which was produced by the as-yet-undescribed marine bacterium of the rare genus Serinicoccus. As part of a long-term research program aimed at the discovery of new agents for the treatment [...] Read more.

The bioactive natural product seriniquinone was discovered as a potential melanoma drug, which was produced by the as-yet-undescribed marine bacterium of the rare genus Serinicoccus. As part of a long-term research program aimed at the discovery of new agents for the treatment of cancer, seriniquinone revealed remarkable in vitro activity against a diversity of cancer cell lines in the US National Cancer Institute 60-cell line screening. Target deconvolution studies defined the seriniquinones as a new class of melanoma-selective agents that act in part by targeting dermcidin (DCD). The targeted DCD peptide has been recently examined and defined as a “pro-survival peptide” in cancer cells. While DCD was first isolated from human skin and thought to be only an antimicrobial peptide, currently DCD has been also identified as a peptide associated with the survival of cancer cells, through what is believed to be a disulfide-based conjugation with proteins that would normally induce apoptosis. However, the significantly enhanced potency of seriniquinone was of particular interest against the melanoma cell lines assessed in the NCI 60-cell line panel. This observed selectivity provided a driving force that resulted in a multidimensional program for the discovery of a usable drug with a new anticancer target and, therefore, a novel mode of action. Here, we provided an overview of the discovery and development efforts to date. Full article

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20 pages, 1764 KiB

Open AccessEditor’s ChoicePerspective

Responsible Research and Innovation Framework, the Nagoya Protocol and Other European Blue Biotechnology Strategies and Regulations: Gaps Analysis and Recommendations for Increased Knowledge in the Marine Biotechnology Community

by Xenia Theodotou Schneider, Belma Kalamujić Stroil, Christiana Tourapi, Céline Rebours, Susana P. Gaudêncio, Lucie Novoveska and Marlen I. Vasquez

Mar. Drugs 2022, 20(5), 290; https://doi.org/10.3390/md20050290 - 26 Apr 2022

Cited by 8 | Viewed by 4825

Abstract

As the quest for marine-derived compounds with pharmacological and biotechnological potential upsurges, the importance of following regulations and applying Responsible Research and Innovation (RRI) also increases. This article aims at: (1) presenting an overview of regulations and policies at the international and EU [...] Read more.

As the quest for marine-derived compounds with pharmacological and biotechnological potential upsurges, the importance of following regulations and applying Responsible Research and Innovation (RRI) also increases. This article aims at: (1) presenting an overview of regulations and policies at the international and EU level, while demonstrating a variability in their implementation; (2) highlighting the importance of RRI in biodiscovery; and (3) identifying gaps and providing recommendations on how to improve the market acceptability and compliance of novel Blue Biotechnology compounds. This article is the result of the work of the Working Group 4 “Legal aspects, IPR and Ethics” of the COST Action CA18238 Ocean4Biotech, a network of more than 130 Marine Biotechnology scientists and practitioners from 37 countries. Three qualitative surveys (“Understanding of the Responsible Research and Innovation concept”, “Application of the Nagoya Protocol in Your Research”, and “Brief Survey about the experiences regarding the Nagoya Protocol”) indicate awareness and application gaps of RRI, the Nagoya Protocol, and the current status of EU policies relating to Blue Biotechnology. The article categorises the identified gaps into five main categories (awareness, understanding, education, implementation, and enforcement of the Nagoya Protocol) and provides recommendations for mitigating them at the European, national, and organisational level. Full article

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15 pages, 7594 KiB

Open AccessEditor’s ChoiceArticle

Discovery of New Secondary Metabolites from Marine Bacteria Hahella Based on an Omics Strategy

by Shufen He, Peishan Li, Jingxuan Wang, Yanzhu Zhang, Hongmei Lu, Liufei Shi, Tao Huang, Weiyan Zhang, Lijian Ding, Shan He and Liwei Liu

Mar. Drugs 2022, 20(4), 269; https://doi.org/10.3390/md20040269 - 18 Apr 2022

Cited by 5 | Viewed by 4102

Abstract

Hahella is one characteristic genus under the Hahellaceae family and shows a good potential for synthesizing new natural products. In this study, we examined the distribution of the secondary metabolite biosynthetic gene cluster (SMBGC) under Hahella with anti-SMASH. The results derived from five [...] Read more.

Hahella is one characteristic genus under the Hahellaceae family and shows a good potential for synthesizing new natural products. In this study, we examined the distribution of the secondary metabolite biosynthetic gene cluster (SMBGC) under Hahella with anti-SMASH. The results derived from five genomes released 70 SMBGCs. On average, each strain contains 12 gene clusters, and the most abundant ones (45.7%) are from the family of non-ribosomal peptide synthetase (NRPS) and non-ribosomal peptide synthetase hybrid with polyketide synthase (NRPS/PKS), indicating a great potential to find bioactive compounds. The comparison of SMBGC between H. chejuensis and other species showed that H. chejuensis contained two times more gene clusters than H. ganghwensis. One strain, designed as NBU794, was isolated from the mangrove soil of Dongzhai Port in Haikou (China) by iChip. The 16S rRNA gene of NBU794 exhibited 99% identity to H. chejuensis KCTC 2396 and clustered with the H. chejuensis clade on the phylogenetic trees. Genome mining on strain NBU794 released 17 SMBGCs and two groups of bioactive compounds, which are chejuenolide A-C and nine prodiginines derivatives. The prodiginines derivatives include the well-known lead compound prodigiosin and two new compounds, 2-methyl-3-pentyl-4-O-methyl-prodiginine and 2-methyl-3-octyl-prodiginine, which were identified through fragmentation analysis based on LC-MS/MS. The anti-microbial activity assay showed prodigiosin and 2-methyl-3-heptyl-prodiginine exhibited the best performance in inhibiting Escherichia coli, Salmonella paratyphi B, MASA Staphylococcus aureus, Bacillus subtilis, and Candida albicans. Moreover, the yield of prodigiosin in H. chejuensis NBU794 was also evaluated, which could reach 1.40 g/L under the non-optimized condition and increase to 5.83 g/L in the modified ISP4 medium with macroporous adsorption beads added, indicating that NBU794 is a promising source of prodigiosin. Full article

(This article belongs to the Special Issue Marine Drug Research in China: Selected Papers from the 15-NASMD Conference)

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30 pages, 10822 KiB

Open AccessEditor’s ChoiceArticle

Cytotoxic Alkylynols of the Sponge Cribrochalina vasculum: Structure, Synthetic Analogs and SAR Studies

by Dimitry Kovalerchik, Ana Zovko, Petra Hååg, Adam Sierakowiak, Kristina Viktorsson, Rolf Lewensohn, Micha Ilan and Shmuel Carmeli

Mar. Drugs 2022, 20(4), 265; https://doi.org/10.3390/md20040265 - 13 Apr 2022

Cited by 2 | Viewed by 2641

Abstract

A series of twenty-three linear and branched chain mono acetylene lipids were isolated from the Caribbean Sea sponge Cribrochalina vasculum. Seventeen of the compounds, 1–17, are new, while six, 18–23, were previously characterized from the same sponge. Some of the [...] Read more.

A series of twenty-three linear and branched chain mono acetylene lipids were isolated from the Caribbean Sea sponge Cribrochalina vasculum. Seventeen of the compounds, 1–17, are new, while six, 18–23, were previously characterized from the same sponge. Some of the new acetylene-3-hydroxy alkanes 1, 6, 7, 8, 10 were tested for selective cytotoxicity in non-small cell lung carcinoma (NSCLC) cells over WI-38 normal diploid lung fibroblasts. Compound 7, presented clear tumor selective activity while, 1 and 8, showed selectivity at lower doses and 6 and 10, were not active towards NSCLC cells at all. The earlier reported selective cytotoxicity of some acetylene-3-hydroxy alkanes (scal-18 and 23), in NSCLC cells and/or other tumor cell types were also confirmed for 19, 20 and 22. To further study the structure activity relationships (SAR) of this group of compounds, we synthesized several derivatives of acetylene-3-hydroxy alkanes, rac-18, scal-S-18, R-18, rac-27, rac-32, R-32, S-32, rac-33, rac-41, rac-42, rac-43, rac-45, rac-48 and rac-49, along with other 3-substituted derivatives, rac-35, rac-36, rac-37, rac-38, rac-39 and rac-40, and assessed their cytotoxic activity against NSCLC cells and diploid fibroblasts. SAR studies revealed that the alcohol moiety at position 3 and its absolute R configuration both were essential for the tumor cell line selective activity while for its cytotoxic magnitude the alkyl chain length and branching were of less significance. Full article

(This article belongs to the Special Issue Marine Sponge Biotechnology)

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35 pages, 4855 KiB

Open AccessFeature PaperEditor’s ChoiceReview

What Was Old Is New Again: The Pennate Diatom Haslea ostrearia (Gaillon) Simonsen in the Multi-Omic Age

by Noujoud Gabed, Frédéric Verret, Aurélie Peticca, Igor Kryvoruchko, Romain Gastineau, Orlane Bosson, Julie Séveno, Olga Davidovich, Nikolai Davidovich, Andrzej Witkowski, Jon Bent Kristoffersen, Amel Benali, Efstathia Ioannou, Aikaterini Koutsaviti, Vassilios Roussis, Hélène Gâteau, Suliya Phimmaha, Vincent Leignel, Myriam Badawi, Feriel Khiar, Nellie Francezon, Mostefa Fodil, Pamela Pasetto and Jean-Luc Mouget Show full author list Hide full author list

Mar. Drugs 2022, 20(4), 234; https://doi.org/10.3390/md20040234 - 29 Mar 2022

Cited by 7 | Viewed by 4599

Abstract

The marine pennate diatom Haslea ostrearia has long been known for its characteristic blue pigment marennine, which is responsible for the greening of invertebrate gills, a natural phenomenon of great importance for the oyster industry. For two centuries, this taxon was considered unique; [...] Read more.

The marine pennate diatom Haslea ostrearia has long been known for its characteristic blue pigment marennine, which is responsible for the greening of invertebrate gills, a natural phenomenon of great importance for the oyster industry. For two centuries, this taxon was considered unique; however, the recent description of a new blue Haslea species revealed unsuspected biodiversity. Marennine-like pigments are natural blue dyes that display various biological activities—e.g., antibacterial, antioxidant and antiproliferative—with a great potential for applications in the food, feed, cosmetic and health industries. Regarding fundamental prospects, researchers use model organisms as standards to study cellular and physiological processes in other organisms, and there is a growing and crucial need for more, new and unconventional model organisms to better correspond to the diversity of the tree of life. The present work, thus, advocates for establishing H. ostrearia as a new model organism by presenting its pros and cons—i.e., the interesting aspects of this peculiar diatom (representative of benthic-epiphytic phytoplankton, with original behavior and chemodiversity, controlled sexual reproduction, fundamental and applied-oriented importance, reference genome, and transcriptome will soon be available); it will also present the difficulties encountered before this becomes a reality as it is for other diatom models (the genetics of the species in its infancy, the transformation feasibility to be explored, the routine methods needed to cryopreserve strains of interest). Full article

(This article belongs to the Special Issue Genetic Approach and Data Mining in Discovery of Marine Natural Products)

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19 pages, 776 KiB

Open AccessEditor’s ChoiceArticle

Identification of New CTX Analogues in Fish from the Madeira and Selvagens Archipelagos by Neuro-2a CBA and LC-HRMS

by Àngels Tudó, Maria Rambla-Alegre, Cintia Flores, Núria Sagristà, Paloma Aguayo, Laia Reverté, Mònica Campàs, Neide Gouveia, Carolina Santos, Karl B. Andree, Antonio Marques, Josep Caixach and Jorge Diogène

Mar. Drugs 2022, 20(4), 236; https://doi.org/10.3390/md20040236 - 29 Mar 2022

Cited by 8 | Viewed by 3211

Abstract

Ciguatera Poisoning (CP) is caused by consumption of fish or invertebrates contaminated with ciguatoxins (CTXs). Presently CP is a public concern in some temperate regions, such as Macaronesia (North-Eastern Atlantic Ocean). Toxicity analysis was performed to characterize the fish species that can accumulate [...] Read more.

Ciguatera Poisoning (CP) is caused by consumption of fish or invertebrates contaminated with ciguatoxins (CTXs). Presently CP is a public concern in some temperate regions, such as Macaronesia (North-Eastern Atlantic Ocean). Toxicity analysis was performed to characterize the fish species that can accumulate CTXs and improve understanding of the ciguatera risk in this area. For that, seventeen fish specimens comprising nine species were captured from coastal waters inMadeira and Selvagens Archipelagos. Toxicity was analysed by screening CTX-like toxicity with the neuroblastoma cell-based assay (neuro-2a CBA). Afterwards, the four most toxic samples were analysed with liquid chromatography-high resolution mass spectrometry (LC-HRMS). Thirteen fish specimens presented CTX-like toxicity in their liver, but only four of these in their muscle. The liver of one specimen of Muraena augusti presented the highest CTX-like toxicity (0.270 ± 0.121 µg of CTX1B equiv·kg⁻¹). Moreover, CTX analogues were detected with LC-HRMS, for M. augusti and Gymnothorax unicolor. The presence of three CTX analogues was identified: C-CTX1, which had been previously described in the area; dihydro-CTX2, which is reported in the area for the first time; a putative new CTX m/z 1127.6023 ([M+NH₄]⁺) named as putative C-CTX-1109, and gambieric acid A. Full article

(This article belongs to the Special Issue Marine Phycotoxins)

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16 pages, 38481 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Discovery of Marine Natural Products as Promising Antibiotics against Pseudomonas aeruginosa

by Haoran Li, Mireguli Maimaitiming, Yue Zhou, Huaxuan Li, Pingyuan Wang, Yang Liu, Till F. Schäberle, Zhiqing Liu and Chang-Yun Wang

Mar. Drugs 2022, 20(3), 192; https://doi.org/10.3390/md20030192 - 4 Mar 2022

Cited by 13 | Viewed by 5926

Abstract

Pseudomonas aeruginosa, one of the most intractable Gram-negative bacteria, has become a public health threat due to its outer polysaccharide layer, efflux transporter system, and high level of biofilm formation, all of which contribute to multi-drug resistance. Even though it is a [...] Read more.

Pseudomonas aeruginosa, one of the most intractable Gram-negative bacteria, has become a public health threat due to its outer polysaccharide layer, efflux transporter system, and high level of biofilm formation, all of which contribute to multi-drug resistance. Even though it is a pathogen of the highest concern, the status of the antibiotic development pipeline is unsatisfactory. In this review, we summarize marine natural products (MNPs) isolated from marine plants, animals, and microorganisms which possess unique structures and promising antibiotic activities against P. aeruginosa. In the last decade, nearly 80 such MNPs, ranging from polyketides to alkaloids, peptides, and terpenoids, have been discovered. Representative compounds exhibited impressive in vitro anti-P. aeruginosa activities with MIC values in the single-digit nanomolar range and in vivo efficacy in infectious mouse models. For some of the compounds, the preliminary structure-activity-relationship (SAR) and anti-bacterial mechanisms of selected compounds were introduced. Compounds that can disrupt biofilm formation or membrane integrity displayed potent inhibition of multi-resistant clinical P. aeruginosa isolates and could be considered as lead compounds for future development. Challenges on how to translate hits into useful candidates for clinical development are also proposed and discussed. Full article

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11 pages, 1482 KiB

Open AccessEditor’s ChoiceArticle

Unveiling the Chemical Diversity of the Deep-Sea Sponge Characella pachastrelloides

by Sam Afoullouss, Anthony R. Sanchez, Laurence K. Jennings, Younghoon Kee, A. Louise Allcock and Olivier P. Thomas

Mar. Drugs 2022, 20(1), 52; https://doi.org/10.3390/md20010052 - 5 Jan 2022

Cited by 2 | Viewed by 5659

Abstract

Sponges are at the forefront of marine natural product research. In the deep sea, extreme conditions have driven secondary metabolite pathway evolution such that we might expect deep-sea sponges to yield a broad range of unique natural products. Here, we investigate the chemodiversity [...] Read more.

Sponges are at the forefront of marine natural product research. In the deep sea, extreme conditions have driven secondary metabolite pathway evolution such that we might expect deep-sea sponges to yield a broad range of unique natural products. Here, we investigate the chemodiversity of a deep-sea tetractinellid sponge, Characella pachastrelloides, collected from ~800 m depth in Irish waters. First, we analyzed the MS/MS data obtained from fractions of this sponge on the GNPS public online platform to guide our exploration of its chemodiversity. Novel glycolipopeptides named characellides were previously isolated from the sponge and herein cyanocobalamin, a manufactured form of vitamin B₁₂, not previously found in nature, was isolated in a large amount. We also identified several poecillastrins from the molecular network, a class of polyketide known to exhibit cytotoxicity. Light sensitivity prevented the isolation and characterization of these polyketides, but their presence was confirmed by characteristic NMR and MS signals. Finally, we isolated the new betaine 6-methylhercynine, which contains a unique methylation at C-2 of the imidazole ring. This compound showed potent cytotoxicity towards against HeLa (cervical cancer) cells. Full article

(This article belongs to the Special Issue Discovering Marine Bioactive Compounds by Molecular Networking)

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26 pages, 2521 KiB

Open AccessEditor’s ChoiceArticle

Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases

by Laura Llorach-Pares, Alfons Nonell-Canals, Conxita Avila and Melchor Sanchez-Martinez

Mar. Drugs 2022, 20(1), 53; https://doi.org/10.3390/md20010053 - 5 Jan 2022

Cited by 7 | Viewed by 4770

Abstract

Computer-aided drug design (CADD) techniques allow the identification of compounds capable of modulating protein functions in pathogenesis-related pathways, which is a promising line on drug discovery. Marine natural products (MNPs) are considered a rich source of bioactive compounds, as the oceans are home [...] Read more.

Computer-aided drug design (CADD) techniques allow the identification of compounds capable of modulating protein functions in pathogenesis-related pathways, which is a promising line on drug discovery. Marine natural products (MNPs) are considered a rich source of bioactive compounds, as the oceans are home to much of the planet’s biodiversity. Biodiversity is directly related to chemodiversity, which can inspire new drug discoveries. Therefore, natural products (NPs) in general, and MNPs in particular, have been used for decades as a source of inspiration for the design of new drugs. However, NPs present both opportunities and challenges. These difficulties can be technical, such as the need to dive or trawl to collect the organisms possessing the compounds, or biological, due to their particular marine habitats and the fact that they can be uncultivable in the laboratory. For all these difficulties, the contributions of CADD can play a very relevant role in simplifying their study, since, for example, no biological sample is needed to carry out an in-silico analysis. Therefore, the amount of natural product that needs to be used in the entire preclinical and clinical study is significantly reduced. Here, we exemplify how this combination between CADD and MNPs can help unlock their therapeutic potential. In this study, using a set of marine invertebrate molecules, we elucidate their possible molecular targets and associated therapeutic potential, establishing a pipeline that can be replicated in future studies. Full article

(This article belongs to the Special Issue Marine Drugs Research in Spain)

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48 pages, 1665 KiB

Open AccessEditor’s ChoiceReview

An Updated Review of Tetrodotoxin and Its Peculiarities

by Panagiota Katikou, Cengiz Gokbulut, Ali Rıza Kosker, Mònica Campàs and Fatih Ozogul

Mar. Drugs 2022, 20(1), 47; https://doi.org/10.3390/md20010047 - 3 Jan 2022

Cited by 66 | Viewed by 15034

Abstract

Tetrodotoxin (TTX) is a crystalline, weakly basic, colorless organic substance and is one of the most potent marine toxins known. Although TTX was first isolated from pufferfish, it has been found in numerous other marine organisms and a few terrestrial species. Moreover, tetrodotoxication [...] Read more.

Tetrodotoxin (TTX) is a crystalline, weakly basic, colorless organic substance and is one of the most potent marine toxins known. Although TTX was first isolated from pufferfish, it has been found in numerous other marine organisms and a few terrestrial species. Moreover, tetrodotoxication is still an important health problem today, as TTX has no known antidote. TTX poisonings were most commonly reported from Japan, Thailand, and China, but today the risk of TTX poisoning is spreading around the world. Recent studies have shown that TTX-containing fish are being found in other regions of the Pacific and in the Indian Ocean, as well as the Mediterranean Sea. This review aims to summarize pertinent information available to date on the structure, origin, distribution, mechanism of action of TTX and analytical methods used for the detection of TTX, as well as on TTX-containing organisms, symptoms of TTX poisoning, and incidence worldwide. Full article

(This article belongs to the Special Issue Marine Phycotoxins)

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12 pages, 1385 KiB

Open AccessEditor’s ChoiceArticle

Bacillimidazoles A−F, Imidazolium-Containing Compounds Isolated from a Marine Bacillus

by Jia-Xuan Yan, Qihao Wu, Eric J. N. Helfrich, Marc G. Chevrette, Doug R. Braun, Heino Heyman, Gene E. Ananiev, Scott R. Rajski, Cameron R. Currie, Jon Clardy and Tim S. Bugni

Mar. Drugs 2022, 20(1), 43; https://doi.org/10.3390/md20010043 - 1 Jan 2022

Cited by 7 | Viewed by 5297

Abstract

Chemical investigations of a marine sponge-associated Bacillus revealed six new imidazolium-containing compounds, bacillimidazoles A–F (1–6). Previous reports of related imidazolium-containing natural products are rare. Initially unveiled by timsTOF (trapped ion mobility spectrometry) MS data, extensive HRMS and 1D and [...] Read more.

Chemical investigations of a marine sponge-associated Bacillus revealed six new imidazolium-containing compounds, bacillimidazoles A–F (1–6). Previous reports of related imidazolium-containing natural products are rare. Initially unveiled by timsTOF (trapped ion mobility spectrometry) MS data, extensive HRMS and 1D and 2D NMR analyses enabled the structural elucidation of 1–6. In addition, a plausible biosynthetic pathway to bacillimidazoles is proposed based on isotopic labeling experiments and invokes the highly reactive glycolytic adduct 2,3-butanedione. Combined, the results of structure elucidation efforts, isotopic labeling studies and bioinformatics suggest that 1–6 result from a fascinating intersection of primary and secondary metabolic pathways in Bacillus sp. WMMC1349. Antimicrobial assays revealed that, of 1–6, only compound six displayed discernible antibacterial activity, despite the close structural similarities shared by all six natural products. Full article

(This article belongs to the Special Issue Heterocyclic Compounds from Marine Organisms)

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15 pages, 1465 KiB

Open AccessEditor’s ChoiceArticle

Not Drug-like, but Like Drugs: Cnidaria Natural Products

by Claire Laguionie-Marchais, A. Louise Allcock, Bill J. Baker, Ellie-Ann Conneely, Sarah G. Dietrick, Fiona Kearns, Kate McKeever, Ryan M. Young, Connor A. Sierra, Sylvia Soldatou, H. Lee Woodcock and Mark P. Johnson

Mar. Drugs 2022, 20(1), 42; https://doi.org/10.3390/md20010042 - 30 Dec 2021

Cited by 6 | Viewed by 3955

Abstract

Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known [...] Read more.

Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known to derive from microbial symbionts), using a systematic approach based on chemical space, drug-likeness, predicted toxicity, and virtual screens. Previous drug-likeness measures: the rule-of-five, quantitative estimate of drug-likeness (QED), and relative drug likelihoods (RDL) are based on a relatively small number of molecular properties. We augmented this approach using reference drug and toxin data sets defined for 51 predicted molecular properties. Cnidaria natural products overlap with drugs and toxins in this chemical space, although a multivariate test suggests that there are some differences between the groups. In terms of the established drug-likeness measures, Cnidaria natural products have generally lower QED and RDL scores than drugs, with a higher prevalence of metabolites that exceed at least one rule-of-five threshold. An index of drug-likeness that includes predicted toxicity (ADMET-score), however, found that Cnidaria natural products were more favourable than drugs. A measure of the distance of individual Cnidaria natural products to the centre of the drug distribution in multivariate chemical space was related to RDL, ADMET-score, and the number of rule-of-five exceptions. This multivariate similarity measure was negatively correlated with the QED score for the same metabolite, suggesting that the different approaches capture different aspects of the drug-likeness of individual metabolites. The contrasting of different drug similarity measures can help summarise the range of drug potential in the Cnidaria natural product data set. The most favourable metabolites were around 210–265 Da, quite often sesquiterpenes, with a moderate degree of complexity. Virtual screening against cancer-relevant targets found wide evidence of affinities, with Glide scores <−7 in 19% of the Cnidaria natural products. Full article

(This article belongs to the Special Issue Reef Ecology and Marine Drug Discovery)

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12 pages, 1969 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Bioactivities and Biosynthesis of Angucycline/Angucyclinone Derivatives Derived from Gephyromycinifex aptenodytis gen. nov., sp. nov.

by Wen-Zhuo Zhu, Shu-Heng Wang, Hui-Min Gao, Ya-Ming Ge, Jun Dai, Xiao-Ling Zhang and Qiao Yang

Mar. Drugs 2022, 20(1), 34; https://doi.org/10.3390/md20010034 - 29 Dec 2021

Cited by 13 | Viewed by 2802

Abstract

Strain NJES-13^T is the type strain and currently the only species of the newly established actinobacteria genera Aptenodytes in the family Dermatophilaceae isolated from the gut microbiota of the Antarctic emperor penguin. This strain demonstrated excellent bioflocculation activity with bacteria-derived exopolysaccharides (EPSs). [...] Read more.

Strain NJES-13^T is the type strain and currently the only species of the newly established actinobacteria genera Aptenodytes in the family Dermatophilaceae isolated from the gut microbiota of the Antarctic emperor penguin. This strain demonstrated excellent bioflocculation activity with bacteria-derived exopolysaccharides (EPSs). Moreover, it produced bioactive angucycline/angucyclinone derivatives (ADs) and contained one type III polyketide synthase (T3PKS), thus demonstrating great potential to produce novel bioactive compounds. However, the low productivity of the potential new AD metabolite was the main obstacle for its chemical structure elucidation. In this study, to increase the concentration of targeted metabolites, the influence of cellular morphology on AD metabolism in strain NJES-13^T was determined using glass bead-enhanced fermentation. Based on the cellular ultra-structural observation driven by bacterial EPSs, and quantitative analysis of the targeted metabolites, the successful increasing of the productivity of three AD metabolites was achieved. Afterward, a new frigocyclinone analogue was isolated and then identified as 2-hydroxy-frigocyclinone, as well as two other known ADs named 2-hydroxy-tetrangomycin (2-HT) and gephyromycin (GPM). Three AD metabolites were found to demonstrate different bioactivities. Both C-2 hydroxyl substitutes, 2-hydroxy-tetrangomycin and 2-hydroxy-frigocyclinone, exhibited variable inhibitory activities against Staphylococcus aureus, Bacillus subtilis and Candida albicans. Moreover, the newly identified 2-hydroxy-frigocyclinone also showed significant cytotoxicity against three tested human-derived cancerous cell lines (HL-60, Bel-7402 and A549), with all obtained IC₅₀ values less than 10 µM. Based on the genetic analysis after genomic mining, the plausible biogenetic pathway of the three bioactive ADs in strain NJES-13^T was also proposed. Full article

(This article belongs to the Special Issue Marine Exopolysaccharides: Health Potential and Other Industrial Applications)

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23 pages, 4241 KiB

Open AccessEditor’s ChoiceReview

Novel Alkaloids from Marine Actinobacteria: Discovery and Characterization

by Anne-Sofie De Rop, Jeltien Rombaut, Thomas Willems, Marilyn De Graeve, Lynn Vanhaecke, Paco Hulpiau, Sofie L. De Maeseneire, Maarten L. De Mol and Wim K. Soetaert

Mar. Drugs 2022, 20(1), 6; https://doi.org/10.3390/md20010006 - 22 Dec 2021

Cited by 11 | Viewed by 6802

Abstract

The marine environment is an excellent resource for natural products with therapeutic potential. Its microbial inhabitants, often associated with other marine organisms, are specialized in the synthesis of bioactive secondary metabolites. Similar to their terrestrial counterparts, marine Actinobacteria are a prevalent source of [...] Read more.

The marine environment is an excellent resource for natural products with therapeutic potential. Its microbial inhabitants, often associated with other marine organisms, are specialized in the synthesis of bioactive secondary metabolites. Similar to their terrestrial counterparts, marine Actinobacteria are a prevalent source of these natural products. Here, we discuss 77 newly discovered alkaloids produced by such marine Actinobacteria between 2017 and mid-2021, as well as the strategies employed in their elucidation. While 12 different classes of alkaloids were unraveled, indoles, diketopiperazines, glutarimides, indolizidines, and pyrroles were most dominant. Discoveries were mainly based on experimental approaches where microbial extracts were analyzed in relation to novel compounds. Although such experimental procedures have proven useful in the past, the methodologies need adaptations to limit the chance of compound rediscovery. On the other hand, genome mining provides a different angle for natural product discovery. While the technology is still relatively young compared to experimental screening, significant improvement has been made in recent years. Together with synthetic biology tools, both genome mining and extract screening provide excellent opportunities for continued drug discovery from marine Actinobacteria. Full article

(This article belongs to the Special Issue Identification of Bioactive Compounds from Marine Actinobacteria and Fungi)

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14 pages, 905 KiB

Open AccessEditor’s ChoiceArticle

Identification and Heterologous Expression of the Kendomycin B Biosynthetic Gene Cluster from Verrucosispora sp. SCSIO 07399

by Jiang Chen, Shanwen Zhang, Yingying Chen, Xinpeng Tian, Yucheng Gu and Jianhua Ju

Mar. Drugs 2021, 19(12), 673; https://doi.org/10.3390/md19120673 - 26 Nov 2021

Cited by 5 | Viewed by 3470

Abstract

Verrucosispora sp. SCSIO 07399, a rare marine-derived actinomycete, produces a set of ansamycin-like polyketides kendomycin B–D (1–3) which possess potent antibacterial activities and moderate tumor cytotoxicity. Structurally, kendomycin B–D contain a unique aliphatic macrocyclic ansa scaffold in which the [...] Read more.

Verrucosispora sp. SCSIO 07399, a rare marine-derived actinomycete, produces a set of ansamycin-like polyketides kendomycin B–D (1–3) which possess potent antibacterial activities and moderate tumor cytotoxicity. Structurally, kendomycin B–D contain a unique aliphatic macrocyclic ansa scaffold in which the highly substituted pyran ring is connected to the quinone moiety. In this work, a type I/type III polyketide synthase (PKS) hybrid biosynthetic gene cluster coding for assembly of kendomycin B (kmy), and covering 33 open reading frames, was identified from Verrucosispora sp. SCSIO 07399. The kmy cluster was found to be essential for kendomycin B biosynthesis as verified by gene disruption and heterologous expression. Correspondingly, a biosynthetic pathway was proposed based on bioinformatics, cluster alignments, and previous research. Additionally, the role of type III PKS for generating the precursor unit 3,5-dihydroxybenzoic acid (3,5-DHBA) was demonstrated by chemical complementation, and type I PKS executed the polyketide chain elongation. The kmy cluster was found to contain a positive regulatory gene kmy4 whose regulatory effect was identified using real-time quantitative PCR (RT-qPCR). These advances shed important new insights into kendomycin B biosynthesis and help to set the foundation for further research aimed at understanding and exploiting the carbacylic ansa scaffold. Full article

(This article belongs to the Special Issue Bioactive Compounds from Marine Streptomyces)

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16 pages, 2101 KiB

Open AccessEditor’s ChoiceArticle

A Novel Angiotensin-I-Converting Enzyme (ACE) Inhibitory Peptide from Takifugu flavidus

by Yongchang Su, Shicheng Chen, Shuilin Cai, Shuji Liu, Nan Pan, Jie Su, Kun Qiao, Min Xu, Bei Chen, Suping Yang and Zhiyu Liu

Mar. Drugs 2021, 19(12), 651; https://doi.org/10.3390/md19120651 - 23 Nov 2021

Cited by 22 | Viewed by 3385

Abstract

Alcalase, neutral protease, and pepsin were used to hydrolyze the skin of Takifugu flavidus. The T. flavidus hydrolysates (TFHs) with the maximum degree of hydrolysis (DH) and angiotensin-I-converting enzyme (ACE)-inhibitory activity were selected and then ultra-filtered to obtain fractions with components of [...] Read more.

Alcalase, neutral protease, and pepsin were used to hydrolyze the skin of Takifugu flavidus. The T. flavidus hydrolysates (TFHs) with the maximum degree of hydrolysis (DH) and angiotensin-I-converting enzyme (ACE)-inhibitory activity were selected and then ultra-filtered to obtain fractions with components of different molecular weights (MWs) (<1, 1–3, 3–10, 10–50, and >50 kDa). The components with MWs < 1 kDa showed the strongest ACE-inhibitory activity with a half-maximal inhibitory concentration (IC₅₀) of 0.58 mg/mL. Purification and identification using semi-preparative liquid chromatography, Sephadex G-15 gel chromatography, RP-HPLC, and LC–MS/MS yielded one new potential ACE-inhibitory peptide, PPLLFAAL (non-competitive suppression mode; IC₅₀ of 28 μmmol·L⁻¹). Molecular docking and molecular dynamics simulations indicated that the peptides should bind well to ACE and interact with amino acid residues and the zinc ion at the ACE active site. Furthermore, a short-term assay of antihypertensive activity in spontaneously hypertensive rats (SHRs) revealed that PPLLFAAL could significantly decrease the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of SHRs after intravenous administration. These results suggested that PPLLFAAL may have potential applications in functional foods or pharmaceuticals as an antihypertensive agent. Full article

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39 pages, 11624 KiB

Open AccessEditor’s ChoiceArticle

Application of Networking Approaches to Assess the Chemical Diversity, Biogeography, and Pharmaceutical Potential of Verongiida Natural Products

by James Lever, Robert Brkljača, Colin Rix and Sylvia Urban

Mar. Drugs 2021, 19(10), 582; https://doi.org/10.3390/md19100582 - 18 Oct 2021

Cited by 6 | Viewed by 3758

Abstract

This study provides a review of all isolated natural products (NPs) reported for sponges within the order Verongiida (1960 to May 2020) and includes a comprehensive compilation of their geographic and physico-chemical parameters. Physico-chemical parameters were used in this study to infer pharmacokinetic [...] Read more.

This study provides a review of all isolated natural products (NPs) reported for sponges within the order Verongiida (1960 to May 2020) and includes a comprehensive compilation of their geographic and physico-chemical parameters. Physico-chemical parameters were used in this study to infer pharmacokinetic properties as well as the potential pharmaceutical potential of NPs from this order of marine sponge. In addition, a network analysis for the NPs produced by the Verongiida sponges was applied to systematically explore the chemical space relationships between taxonomy, secondary metabolite and drug score variables, allowing for the identification of differences and correlations within a dataset. The use of scaffold networks as well as bipartite relationship networks provided a platform to explore chemical diversity as well as the use of chemical similarity networks to link pharmacokinetic properties with structural similarity. This study paves the way for future applications of network analysis procedures in the field of natural products for any order or family. Full article

(This article belongs to the Special Issue Marine Drug Discovery through Computer-Aided Approaches)

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17 pages, 4138 KiB

Open AccessEditor’s ChoiceArticle

Posidonia oceanica (L.) Delile Dampens Cell Migration of Human Neuroblastoma Cells

by Marzia Vasarri, Manuela Leri, Emanuela Barletta, Carlo Pretti and Donatella Degl’Innocenti

Mar. Drugs 2021, 19(10), 579; https://doi.org/10.3390/md19100579 - 15 Oct 2021

Cited by 7 | Viewed by 3261

Abstract

Neuroblastoma (NB) is a common cancer in childhood, and lethal in its high-risk form, primarily because of its high metastatic potential. Targeting cancer cell migration, and thus preventing metastasis formation, is the rationale for more effective cancer therapy against NB. Previous studies have [...] Read more.

Neuroblastoma (NB) is a common cancer in childhood, and lethal in its high-risk form, primarily because of its high metastatic potential. Targeting cancer cell migration, and thus preventing metastasis formation, is the rationale for more effective cancer therapy against NB. Previous studies have described the leaf extract from Posidonia oceanica marine plant (POE) as an antioxidant, anti-inflammatory agent and inhibitor of cancer cell migration. This study aims to examine the POE anti-migratory role in human SH-SY5Y neuroblastoma cells and the underlying mechanisms of action. Wound healing and gelatin zymography assays showed that POE at early times inhibits cell migration and reduces pro-MMP-2 release into culture medium. By monitoring expression level of key autophagy markers by Western blot assay, a correlation between POE-induced cell migration inhibition and autophagy activation was demonstrated. Cell morphology and immunofluorescence analyses showed that POE induces neurite formation and neuronal differentiation at later times. These results suggest POE might act against cell migration by triggering early nontoxic autophagy. The POE-induced cellular morphological change toward cell differentiation might contribute to prolonging the phytocomplex anti-migratory effect to later times. Overall, these results encourage future in vivo studies to test POE applicability in neuroblastoma treatment. Full article

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49 pages, 2135 KiB

Open AccessEditor’s ChoiceReview

Anti-Inflammatory and Anticancer Effects of Microalgal Carotenoids

by Javier Ávila-Román, Sara García-Gil, Azahara Rodríguez-Luna, Virginia Motilva and Elena Talero

Mar. Drugs 2021, 19(10), 531; https://doi.org/10.3390/md19100531 - 23 Sep 2021

Cited by 76 | Viewed by 8567

Abstract

Acute inflammation is a key component of the immune system’s response to pathogens, toxic agents, or tissue injury, involving the stimulation of defense mechanisms aimed to removing pathogenic factors and restoring tissue homeostasis. However, uncontrolled acute inflammatory response may lead to chronic inflammation, [...] Read more.

Acute inflammation is a key component of the immune system’s response to pathogens, toxic agents, or tissue injury, involving the stimulation of defense mechanisms aimed to removing pathogenic factors and restoring tissue homeostasis. However, uncontrolled acute inflammatory response may lead to chronic inflammation, which is involved in the development of many diseases, including cancer. Nowadays, the need to find new potential therapeutic compounds has raised the worldwide scientific interest to study the marine environment. Specifically, microalgae are considered rich sources of bioactive molecules, such as carotenoids, which are natural isoprenoid pigments with important beneficial effects for health due to their biological activities. Carotenoids are essential nutrients for mammals, but they are unable to synthesize them; instead, a dietary intake of these compounds is required. Carotenoids are classified as carotenes (hydrocarbon carotenoids), such as α- and β-carotene, and xanthophylls (oxygenate derivatives) including zeaxanthin, astaxanthin, fucoxanthin, lutein, α- and β-cryptoxanthin, and canthaxanthin. This review summarizes the present up-to-date knowledge of the anti-inflammatory and anticancer activities of microalgal carotenoids both in vitro and in vivo, as well as the latest status of human studies for their potential use in prevention and treatment of inflammatory diseases and cancer. Full article

(This article belongs to the Special Issue Marine Carotenoids in Inflammation and Cancer)

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25 pages, 7049 KiB

Open AccessEditor’s ChoiceReview

Methods in Microbial Biodiscovery

by Angela A. Salim, Zeinab G. Khalil, Ahmed H. Elbanna, Taizong Wu and Robert J. Capon

Mar. Drugs 2021, 19(9), 503; https://doi.org/10.3390/md19090503 - 3 Sep 2021

Cited by 19 | Viewed by 4779

Abstract

This review presents an account of the microbial biodiscovery methodology developed and applied in our laboratory at The University of Queensland, Institute for Molecular Bioscience, with examples drawn from our experiences studying natural products produced by Australian marine-derived (and terrestrial) fungi and bacteria. [...] Read more.

This review presents an account of the microbial biodiscovery methodology developed and applied in our laboratory at The University of Queensland, Institute for Molecular Bioscience, with examples drawn from our experiences studying natural products produced by Australian marine-derived (and terrestrial) fungi and bacteria. Full article

(This article belongs to the Special Issue Fungal Natural Products: An Ongoing Source for New Drug Leads)

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19 pages, 4293 KiB

Open AccessEditor’s ChoiceArticle

Toxicity Screening of a Gambierdiscus australes Strain from the Western Mediterranean Sea and Identification of a Novel Maitotoxin Analogue

by Pablo Estevez, David Castro, José Manuel Leão-Martins, Manoëlla Sibat, Angels Tudó, Robert Dickey, Jorge Diogene, Philipp Hess and Ana Gago-Martinez

Mar. Drugs 2021, 19(8), 460; https://doi.org/10.3390/md19080460 - 15 Aug 2021

Cited by 19 | Viewed by 4125

Abstract

Dinoflagellate species of the genera Gambierdiscus and Fukuyoa are known to produce ciguatera poisoning-associated toxic compounds, such as ciguatoxins, or other toxins, such as maitotoxins. However, many species and strains remain poorly characterized in areas where they were recently identified, such as the [...] Read more.

Dinoflagellate species of the genera Gambierdiscus and Fukuyoa are known to produce ciguatera poisoning-associated toxic compounds, such as ciguatoxins, or other toxins, such as maitotoxins. However, many species and strains remain poorly characterized in areas where they were recently identified, such as the western Mediterranean Sea. In previous studies carried out by our research group, a G. australes strain from the Balearic Islands (Mediterranean Sea) presenting MTX-like activity was characterized by LC-MS/MS and LC-HRMS detecting 44-methyl gambierone and gambieric acids C and D. However, MTX1, which is typically found in some G. australes strains from the Pacific Ocean, was not detected. Therefore, this study focuses on the identification of the compound responsible for the MTX-like toxicity in this strain. The G. australes strain was characterized not only using LC-MS instruments but also N2a-guided HPLC fractionation. Following this approach, several toxic compounds were identified in three fractions by LC-MS/MS and HRMS. A novel MTX analogue, named MTX5, was identified in the most toxic fraction, and 44-methyl gambierone and gambieric acids C and D contributed to the toxicity observed in other fractions of this strain. Thus, G. australes from the Mediterranean Sea produces MTX5 instead of MTX1 in contrast to some strains of the same species from the Pacific Ocean. No CTX precursors were detected, reinforcing the complexity of the identification of CTXs precursors in these regions. Full article

(This article belongs to the Special Issue Novel Methods for Marine Toxins Detection and Quantification)

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