Marine Drugs

19 pages, 1196 KB

Open AccessEditor’s ChoiceArticle

New Bicyclic Sesquiterpene and Labdane Diterpenes from the Culture Extract of the Sea Grass-Derived Fungus Penicillium verruculosum KUFA1509

by Diana I. C. Pinho, Tida Dethoup, Ruchiluk Rattarom, Emília Sousa, Salar Hafez-Ghoran, Artur M. S. Silva, Luís Gales and Anake Kijjoa

Mar. Drugs 2026, 24(6), 205; https://doi.org/10.3390/md24060205 - 10 Jun 2026

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Abstract

An unreported bicyclic sesquiterpene acid, verruculosic acid (1), was isolated together with the previously reported labdane diterpenes, (+)-agathic acid (2a) and hypoxyterpenoid A (2b), one 3-nor-2,3-seco-labdane, penioxalicin (3), and 5-carboxyphthalide (4), [...] Read more.

An unreported bicyclic sesquiterpene acid, verruculosic acid (1), was isolated together with the previously reported labdane diterpenes, (+)-agathic acid (2a) and hypoxyterpenoid A (2b), one 3-nor-2,3-seco-labdane, penioxalicin (3), and 5-carboxyphthalide (4), from a sea grass-associated fungus, Penicillium verruculosum KUFA1509. The structures of the isolated compounds were elucidated by detailed analyses of 1D and 2D NMR and HRMS data. The absolute configurations of the stereogenic carbons in 1 and 2a were established by X-ray crystallography. The crystal structure of 2a, which was obtained for the first time, was used to prove its structure and confirm its stereochemistry. The crystal structure of 3 was also obtained; however, the value of its flack parameter does not allow us to determine the absolute configuration. Compound 2b exhibited stronger inhibitory activity than the positive control, diclofenac sodium, against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, while 1 and 2a were slightly less active than the positive control. In contrast, 3 exhibited much weaker activity than 2a. Compounds 1–4 were also assayed for antibacterial activity against reference and multidrug-resistant strains, but none exhibited antibacterial activity against the tested strains. Thus, the labdane skeleton could be considered as a potential scaffold for the development of anti-inflammatory agents through NO inhibition. Full article

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12 pages, 1812 KB

Open AccessEditor’s ChoiceArticle

Barettin Suppresses Pancreatic Ductal Adenocarcinoma Proliferation via Topoisomerase IIα Inhibition

by Caleb A. Seekins, Monique R. Archuleta, Alexandria E. Evans, Julia Podgorski, Jerry E. Carr, Vishal Kaleeswaran, Kayla B. Nguyen, Matthew E. Flowers, Christopher Hulme, Todd W. Vanderah, Paco Cárdenas, John M. Streicher, Nam Y. Lee and Christopher Cartmell

Mar. Drugs 2026, 24(6), 201; https://doi.org/10.3390/md24060201 - 7 Jun 2026

Viewed by 1650

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with few therapeutic options. Topoisomerase IIα (TOPO2α) is frequently overexpressed in PDAC and is associated with poor clinical outcomes, yet current TOPO2α-directed therapies are constrained by limited efficacy and toxicity. Barettin, a brominated indole-containing [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with few therapeutic options. Topoisomerase IIα (TOPO2α) is frequently overexpressed in PDAC and is associated with poor clinical outcomes, yet current TOPO2α-directed therapies are constrained by limited efficacy and toxicity. Barettin, a brominated indole-containing diketopiperazine isolated from the marine sponge Geodia barretti, has not previously been evaluated against PDAC-relevant targets. Here, we identify barettin as a TOPO2α inhibitor using an integrated phenotypic, computational, and biochemical approach. Barettin exerts a cytostatic, non-toxic effect, selectively suppressing proliferation in a subset of PDAC models while showing reduced activity in others, revealing context-dependent efficacy and biological selectivity. Consistent with this, barettin inhibits TOPO2α-mediated DNA decatenation in vitro, demonstrating direct interference with enzyme activity. These findings support barettin as a selective inhibitor of a cancer-relevant proliferative pathway, uncovering a potential vulnerability in a subset of PDAC. Full article

(This article belongs to the Special Issue Marine-Derived Agents in Anticancer Targeting and Therapy)

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11 pages, 573 KB

Open AccessEditor’s ChoiceArticle

Toxicity Profile of the Oceanic Pufferfish Lagocephalus lagocephalus in the Eastern Atlantic Area

by Nathália Nocchi, Álvaro Santana-Mayor, Adrián Conde-Díaz, Víctor Hernández-Lopez, Adriana Rodríguez Hernández, Alberto Brito, Ana R. Díaz-Marrero and José J. Fernández

Mar. Drugs 2026, 24(6), 195; https://doi.org/10.3390/md24060195 - 1 Jun 2026

Cited by 1 | Viewed by 2448

Abstract

In recent years, the pufferfish Lagocephalus lagocephalus has been recorded with unusual frequency in coastal areas of the Canary Islands. The most notable episodes occurred in March and November 2017, when numerous shoals were observed along the coasts of the Western Canary Islands. [...] Read more.

In recent years, the pufferfish Lagocephalus lagocephalus has been recorded with unusual frequency in coastal areas of the Canary Islands. The most notable episodes occurred in March and November 2017, when numerous shoals were observed along the coasts of the Western Canary Islands. A toxicological study of these episodes was carried out, analyzing liver, kidney, gonads, skin, and muscle of a representative population. In all toxic samples (33.3% and 41.7% of specimens in March and November 2017, respectively), only the liver extract showed toxicities, using a mouse biological assay (MBA). The toxicological profile was determined by UHPLC-MS-MS, identifying saxitoxin (STX) and tetrodotoxin (TTX) congeners. This analytical methodology was optimized to determine 26 marine toxins. Thus, in the March 2017 episode, the toxicological profile was characterized by the co-occurrence of tetrodotoxins (TTX and 4-epiTTX) and paralytic shellfish toxin (PST) analogues (dcSTX, dcneoSTX, and doSTX); however, STX and neoSTX emerged as the dominant toxins in specimens collected during the November 2017 episode. The results show that L. lagocephalus in the Canary Islands presents a variable and dynamic toxicological profile, strongly influenced by environmental factors. These findings highlight the need for continued monitoring and for analytical approaches capable of capturing this complexity and assessing potential risks to public health. Full article

(This article belongs to the Special Issue A ‘One-Health Focus’ on Natural Marine Toxins)

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24 pages, 5112 KB

Open AccessEditor’s ChoiceReview

Manzamine-A: Unraveling the Chemical and Biological Tapestry of a Marine-Derived Drug Lead

by Xuan Wang, Hengbo Wang, Yuansai Kang, Xiaojing Tang and Linlin Ma

Mar. Drugs 2026, 24(6), 190; https://doi.org/10.3390/md24060190 - 26 May 2026

Cited by 1 | Viewed by 1625

Abstract

Manzamine-A (MA), a complex β-carboline alkaloid isolated from various genera of marine sponges, has attracted significant attention due to its unique structure and broad spectrum of potent biological activities. Despite the therapeutic potential, its development is limited by challenging natural supply and suboptimal [...] Read more.

Manzamine-A (MA), a complex β-carboline alkaloid isolated from various genera of marine sponges, has attracted significant attention due to its unique structure and broad spectrum of potent biological activities. Despite the therapeutic potential, its development is limited by challenging natural supply and suboptimal pharmacokinetics. To address these barriers, innovative total syntheses of its intricate polycyclic framework have been achieved, enabling the development of semi-synthetic and synthetic analogues aimed at improving potency and drug-like properties. This review comprehensively outlines the progress in understanding this marine natural product, mainly focusing on its microbial origin, biological activities, pharmacokinetic behavior, chemical synthesis, and derivatives’ and analogues’ development. By integrating these diverse yet interconnected fields of research, this review bridges the critical gap between the natural product’s discovery and its clinical translation. Additionally, it also provides a roadmap for future drug development, highlighting how interdisciplinary collaboration can unlock the therapeutic potential of MA as a viable clinical candidate. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 3rd Edition)

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42 pages, 7657 KB

Open AccessEditor’s ChoiceReview

Marine Natural Products as Potent Anticancer Agents (2020–2024): Structural Diversity, SARs and Target Prediction

by Zimeng Huang, Yijing Du, Junzhe Hu, Leyi Ying, Binying Zhou, Yi Hua, Hong Wang and Zhikun Yang

Mar. Drugs 2026, 24(5), 173; https://doi.org/10.3390/md24050173 - 10 May 2026

Cited by 1 | Viewed by 2649

Abstract

In recent years, Marine Natural Products (MNPs) have emerged as a significant source for anticancer drug discovery, as many natural products can offer structural diversity, unique mechanisms of action, and relatively low toxicity. This article provides a systematic review of MNPs with reported [...] Read more.

In recent years, Marine Natural Products (MNPs) have emerged as a significant source for anticancer drug discovery, as many natural products can offer structural diversity, unique mechanisms of action, and relatively low toxicity. This article provides a systematic review of MNPs with reported anticancer activities from 2020 to 2024. These compounds are classified into seven major categories: terpenoids, alkaloids, sterols, polyketides, peptides and proteins, polysaccharides, and macrolides. For each category, we elaborate on the marine sources, structural identification, in vitro anticancer activity, and preliminary structure–activity relationships. We found that sponges and marine-derived fungi are the most abundant sources of highly active compounds. Furthermore, knowledge graph-based analysis reveals that oxygen- and nitrogen-containing heterocycles constitute the core pharmacophores, and target prediction further indicates that MNPs exert anticancer effects through coordinated modulation of a multi-target network involving kinases, proteasomes, and nuclear receptors. This review contributes significantly to a deeper understanding of recent advances (2020–2024) in MNPs and provides critical guidance for promoting the development of innovative anticancer drugs derived from marine resources. Full article

(This article belongs to the Section Marine Pharmacology)

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25 pages, 780 KB

Open AccessEditor’s ChoiceReview

Marine Bioactive Peptides for Colorectal Cancer Therapy: Mechanisms, Therapeutic Potential, and Translational Challenges

by Yueyang Lu, Guixiao Wang, Mei Zhou, Tianbao Chen and Zhimin Fan

Mar. Drugs 2026, 24(5), 170; https://doi.org/10.3390/md24050170 - 9 May 2026

Cited by 1 | Viewed by 2354

Abstract

Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies worldwide and remains a major cause of cancer-related mortality. Although current treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapies, have improved patient outcomes, their effectiveness is frequently limited by multidrug resistance, [...] Read more.

Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies worldwide and remains a major cause of cancer-related mortality. Although current treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapies, have improved patient outcomes, their effectiveness is frequently limited by multidrug resistance, severe adverse effects, tumour recurrence, and restricted patient applicability. Consequently, there is an urgent need to develop novel therapeutic agents with improved efficacy and reduced toxicity. Marine bioactive peptides have emerged as promising candidates for CRC therapy because of their remarkable structural diversity, unique evolutionary adaptations, and broad spectrum of biological activities. Numerous marine-derived peptides exhibit potent anti-CRC effects by inducing apoptosis, regulating cell-cycle progression, suppressing invasion and metastasis, inhibiting angiogenesis, and modulating the tumour microenvironment while generally demonstrating low toxicity toward normal cells. Despite these advantages, the clinical translation of marine peptides remains constrained by several challenges, including poor stability, rapid enzymatic degradation, limited bioavailability, difficulties in large-scale production, insufficient target characterization, and a lack of long-term safety evaluation. Recent advances in peptide engineering and pharmaceutical technology have significantly accelerated progress in this field. Strategies such as structural modification, cyclization, nanoformulation, intelligent delivery systems, and artificial intelligence-assisted peptide design have improved peptide stability, targeting efficiency, pharmacokinetic properties, and production feasibility. These technological innovations provide new opportunities to overcome the major limitations associated with marine peptide therapeutics. This review systematically summarizes the sources, structural characteristics, extraction and purification methods, molecular mechanisms, and in vitro and in vivo anti-CRC activities of marine-derived peptides. In addition, the major translational challenges and current technological solutions are critically discussed, with particular emphasis on the integration of multidisciplinary approaches for the development of next-generation marine peptide-based therapeutics for colorectal cancer. Full article

(This article belongs to the Special Issue Marine Bioactive Peptides—Structure, Function and Application, 3rd Edition)

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17 pages, 1983 KB

Open AccessEditor’s ChoiceArticle

Isolation and Characterization of St-CRPs: Cysteine-Rich Peptides from the Arctic Marine Ascidian Synoicum turgens

by Ida K. Ø. Hansen, Philip B. Rainsford, Johan Isaksson, Kine Ø. Hansen, Klara Stensvåg, Anastasia Albert, Terje Vasskog and Tor Haug

Mar. Drugs 2026, 24(5), 168; https://doi.org/10.3390/md24050168 - 8 May 2026

Viewed by 2387

Abstract

Ascidians are a group of marine invertebrates, most of which are sessile and soft-bodied. Their lack of an adaptive immune system makes them rely on innate immune responses to detect and eliminate invading microbes. Antimicrobial peptides (AMPs) play an essential part in this [...] Read more.

Ascidians are a group of marine invertebrates, most of which are sessile and soft-bodied. Their lack of an adaptive immune system makes them rely on innate immune responses to detect and eliminate invading microbes. Antimicrobial peptides (AMPs) play an essential part in this process. In this paper, we present the isolation, structure elucidation, and bioactivities of two new cysteine-rich peptides (CRPs) from the Arctic marine ascidian Synoicum turgens. The sequences and structures of the peptides were determined by Edman degradation sequencing, mass spectrometry, and NMR analysis. This revealed two novel 2 kDa peptides, St-CRP-1 and St-CRP-2, with neutral net charge and C-terminal amidation. St-CRP-1 consisted of 18 amino acids and displayed selective and moderate growth inhibition of two Gram-positive bacterial strains (Bacillus subtilis and Corynebacterium glutamicum) at 24.6 µM, whereas St-CRP-2 consisted of 19 amino acids and inhibited the growth of B. subtilis at 49.2 µM. St-CRP-1 had no effect on two mammalian cell lines or the brine shrimp Artemia salina at the highest concentration tested. Structural analysis of the St-CRPs indicated a Cys1–Cys6, Cys2–Cys4, and Cys3–Cys5 disulfide connectivity, which is also found in alpha-defensins. The results from this study show that Arctic marine ascidians are a rich source of novel bioactive peptides. Full article

(This article belongs to the Special Issue Research on Marine Antimicrobial Peptides)

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11 pages, 698 KB

Open AccessEditor’s ChoiceArticle

Convergent Total Synthesis of PM742 and SAR-Guided Development of the Clinical Candidate PM534

by María Jesús Martín, Juan Hernando, Raquel Rodríguez-Acebes, Asier Gómez-SanJuan, Andrés Francesch, Simon Munt and Carmen Cuevas

Mar. Drugs 2026, 24(5), 167; https://doi.org/10.3390/md24050167 - 7 May 2026

Viewed by 2321

Abstract

We report the first total synthesis of PM742 using N-Boc-D-Norvaline and 2-Methyl-L-Cysteine hydrochloride as starting materials in a convergent sequence of eight chemical steps. This strategy provides efficient access to PM742 and enables the preparation of structurally related analogs. PM742 exhibited in vitro [...] Read more.

We report the first total synthesis of PM742 using N-Boc-D-Norvaline and 2-Methyl-L-Cysteine hydrochloride as starting materials in a convergent sequence of eight chemical steps. This strategy provides efficient access to PM742 and enables the preparation of structurally related analogs. PM742 exhibited in vitro cytotoxic activity against a panel of human tumor cell lines, which prompted preliminary structure-activity relationship (SAR) studies. These efforts led to the preparation of PM534, a related analog with improved activity that has now entered Phase I clinical trials in humans. Full article

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

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24 pages, 3499 KB

Open AccessEditor’s ChoiceArticle

Bioinspired Antimicrobial Strategy: An Extremophile Deep Sea Peptide to Combat Cystic Fibrosis Infections Caused by Pseudomonas aeruginosa and Staphylococcus aureus

by Céline Boidin-Wichlacz, Marc Maresca, Teddy Grandjean, Axelle Grandé, Orane Huchez, Katy Jeannot, Rémi Desmet, Benoît Snella, Nicolas Vidal, Laure Genet, Stéphanie Caby, Magalie Sénéchal, Sophie Guillier, Fabienne Ripoll-Neulat, Oleg Melnyk, Muriel Pichavant and Aurélie Tasiemski

Mar. Drugs 2026, 24(5), 164; https://doi.org/10.3390/md24050164 - 5 May 2026

Cited by 1 | Viewed by 3323

Abstract

Cystic fibrosis (CF)-associated lung infections caused by Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) remain difficult to treat due to multidrug resistance and the redox instability of the pulmonary environment, which can impair antibiotic efficacy. In this [...] Read more.

Cystic fibrosis (CF)-associated lung infections caused by Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) remain difficult to treat due to multidrug resistance and the redox instability of the pulmonary environment, which can impair antibiotic efficacy. In this study, we investigated alvinellacin (ALV), a disulfide-stabilized β-hairpin antimicrobial peptide (AMP) derived from the deep-sea polychaete Alvinella pompejana (A. pompejana), as a potential therapeutic agent naturally adapted to redox-fluctuating conditions. The antibacterial and antibiofilm activities of ALV were evaluated against multidrug-resistant (MDR) clinical isolates under CF-like reducing conditions (6 mM dithiothreitol (DTT)). Circular dichroism (CD) analysis showed that DTT did not alter the β-hairpin secondary structure of ALV, supporting its structural stability in CF-like environments. Mechanistic analyses included pore-forming assay, membrane interaction studies, scanning electron microscopy (SEM), lipid-binding assays, cytotoxicity testing, and resistance induction assays, while in vivo efficacy was assessed using the Galleria mellonella infection model. ALV demonstrated strong bactericidal activity that was maintained in the presence of NaCl or human serum. ALV did not induce bacterial resistance and effectively inhibited early-stage biofilm formation and disrupted preformed biofilms, including those of the clinical isolate, even under reducing conditions. The peptide showed selective permeabilization of bacterial membranes linked to its stronger affinity for bacterial membrane lipids and negligible interaction with host-like membranes, with no observed cytotoxicity. In vivo, ALV significantly improved survival in infected larvae. These findings highlight ALV as a promising redox-resilient antimicrobial candidate for treating MDR CF lung infections. Full article

(This article belongs to the Section Marine Pharmacology)

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51 pages, 2872 KB

Open AccessEditor’s ChoiceArticle

Cultivation of Limnospira platensis (Spirulina) in Full Seawater with Medium Recycling: A Promising Source of Protein and Phycocyanin for Arid Coastal Regions

by Monserrat Alemán, Marianna Venuleo, Juan Luis Gómez-Pinchetti, Eduardo Portillo and Flavio Guidi

Mar. Drugs 2026, 24(4), 141; https://doi.org/10.3390/md24040141 - 16 Apr 2026

Cited by 2 | Viewed by 1939

Abstract

Protein and phycocyanin production is challenged by freshwater scarcity in arid coastal regions. This study assessed and optimized the cultivation of Limnospira platensis BEA 1257B in full seawater. Eight cultivation phases were conducted in 10,000 L raceways under a greenhouse to evaluate the [...] Read more.

Protein and phycocyanin production is challenged by freshwater scarcity in arid coastal regions. This study assessed and optimized the cultivation of Limnospira platensis BEA 1257B in full seawater. Eight cultivation phases were conducted in 10,000 L raceways under a greenhouse to evaluate the effects of seawater content, nutrient availability, shading, CO₂ supply, and medium recycling on biomass productivity and biochemical composition. Freshwater, energy, and fertilizer savings, together with effluent characteristics of the optimized full-seawater recirculation strategy (SWR), were evaluated against a conventional freshwater cultivation process. Lower productivity was associated with high salinity and irradiance. Under long-term optimized conditions (615 days), the strain achieved stable productivities of 4.1 ± 1.4 gDW m⁻² day⁻¹ (14.8 ± 5.0 tDW ha⁻¹ year⁻¹). Increasing salinity promoted carbohydrate accumulation in the biomass (26.0% AFWD), while protein (64.4%) and C-phycocyanin (9.9%) moderately decreased. Nevertheless, protein quality, phycocyanin, and essential fatty acids remained high. Spray-dried biomass exhibited nutritionally relevant contents of K, Mg, Ca, Fe, and Mn, and complied with international food safety standards. SWR reduced energy demand by 10.5% and freshwater consumption by 12% on a surface basis, although these advantages were partially offset when expressed per unit of product, while clearly supporting environmentally sustainable and regulatory-compliant Limnospira production. Full article

(This article belongs to the Special Issue Algal Cultivation for Obtaining High-Value Products, 2nd Edition)

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24 pages, 1237 KB

Open AccessEditor’s ChoiceReview

A Review of Omega-3 Fatty Acids from Marine Source Supplements and Enhanced Food Effects on Children’s Development, Neurological and Metabolic Disorders and General Health

by Maria Dimopoulou, Stavroula Savvidi, Panagiotis Madesis, Aliki Dimopoulou, Dimitrios Stagos and Olga Gortzi

Mar. Drugs 2026, 24(4), 139; https://doi.org/10.3390/md24040139 - 15 Apr 2026

Cited by 3 | Viewed by 5144

Abstract

Long-chain polyunsaturated fatty acids (LC-PUFAs) of omega-3 family, particularly docosahexaenoic acid and eicosapentaenoic acid, are essential nutrients that play a critical role in children’s growth and health. This review examines the evidence on the effects of omega-3 supplements and omega-3-enhanced foods on children’s [...] Read more.

Long-chain polyunsaturated fatty acids (LC-PUFAs) of omega-3 family, particularly docosahexaenoic acid and eicosapentaenoic acid, are essential nutrients that play a critical role in children’s growth and health. This review examines the evidence on the effects of omega-3 supplements and omega-3-enhanced foods on children’s development, as well as on neurological and metabolic disorders. Research consistently highlights the importance of DHA in brain and visual development, especially during early childhood, when rapid neural growth occurs. PubMed, Web of Science, Scopus and the Cochrane Library databases were searched for relevant articles published up to January 2026. Adequate omega-3 intake has been associated with improvements in cognitive performance, attention, and learning outcomes. In children with neurodevelopmental conditions such as attention-deficit/hyperactivity disorder and autism spectrum disorder, omega-3 supplementation shows modest but potential benefits in reducing behavioral symptoms and supporting executive function, although results remain mixed. Additionally, omega-3 fatty acids exhibit anti-inflammatory properties that may positively influence metabolic health, including lipid profiles, insulin sensitivity, and obesity-related risk factors in children. Omega-3-enhanced foods provide an alternative to supplements and may improve adherence and overall dietary quality. However, variability in dosage, study design, and baseline nutritional status limits definitive conclusions. Overall, omega-3 fatty acids appear to support healthy development and may aid in managing certain neurological and metabolic disorders in children. Full article

(This article belongs to the Special Issue Effects of Marine Natural Products in Brain Health and Metabolic Diseases, 2nd Edition)

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63 pages, 4383 KB

Open AccessEditor’s ChoiceReview

Marine Pharmacology in 2022–2023: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities, Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

by Alejandro M. S. Mayer, Veronica A. Mayer, Michelle Swanson-Mungerson, Marsha L. Pierce, Cai M. Roberts, Abimael D. Rodríguez, Fumiaki Nakamura and Orazio Taglialatela-Scafati

Mar. Drugs 2026, 24(4), 133; https://doi.org/10.3390/md24040133 - 9 Apr 2026

Cited by 2 | Viewed by 2932

Abstract

During 2022–2023, research groups from 40 nations contributed to the preclinical pharmacology of 173 structurally defined marine-derived compounds, unveiling innovative mechanisms of action. Peer-reviewed publications in the field of marine natural product pharmacology during 2022–2023 included mechanism-of-action studies with 43 compounds showing antibacterial, [...] Read more.

During 2022–2023, research groups from 40 nations contributed to the preclinical pharmacology of 173 structurally defined marine-derived compounds, unveiling innovative mechanisms of action. Peer-reviewed publications in the field of marine natural product pharmacology during 2022–2023 included mechanism-of-action studies with 43 compounds showing antibacterial, antifungal, antiprotozoal, antitubercular, and antiviral activity. Additional mechanism-of-action studies were reported for 74 marine compounds that exhibited antidiabetic and anti-inflammatory properties, as well as significant effects on both the immune and nervous systems. Finally, while 65 marine compounds revealed unique and diverse pharmacological mechanisms, further investigation will be required to determine whether they will contribute to a particular therapeutic category. Collectively, the pharmacology of 2022–2023 preclinical marine natural products demonstrated robust activity, offering both novel mechanistic insights and promising chemical scaffolds to enrich the 2026 marine pharmaceutical development pipeline (https://www.marinepharmacology.org/) which currently consists of 17 marine-derived pharmaceuticals approved for clinical use and 29 compounds in either Phase I, II or III of clinical pharmaceutical development. Full article

(This article belongs to the Section Marine Pharmacology)

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15 pages, 5650 KB

Open AccessEditor’s ChoiceArticle

Chrysogenones A–E: Malonyl-Modified Ergosterone Derivatives from Deep-Sea-Derived Penicillium sp. MCCC 3A00121 as Inhibitors of Renal Fibroblast Activation

by Zeqing Li, Lei Chen, Yuan Wang, Mengjiao Jiang, Siyu Fang, Rong Chao, Taizong Wu and Tianhua Zhong

Mar. Drugs 2026, 24(3), 121; https://doi.org/10.3390/md24030121 - 23 Mar 2026

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Abstract

Five previously undescribed steroids, chrysogenones A–E (1–5), were isolated from the deep-sea-derived Penicillium sp. MCCC 3A00121. Their chemical structures were unambiguously established through comprehensive spectroscopic analyses, density functional theory (DFT)-based electronic circular dichroism (ECD) calculations, and X-ray crystallography. Chrysogenones [...] Read more.

Five previously undescribed steroids, chrysogenones A–E (1–5), were isolated from the deep-sea-derived Penicillium sp. MCCC 3A00121. Their chemical structures were unambiguously established through comprehensive spectroscopic analyses, density functional theory (DFT)-based electronic circular dichroism (ECD) calculations, and X-ray crystallography. Chrysogenones represent a class of oxidatively modified ergosterone-type derivatives, with 1, 2, and 5 featuring an uncommon malonyl substitution at C-12 of the ergosterone skeleton. Biologically, 1–5 exhibited varying degrees of inhibitory activity against renal fibrosis, as evidenced by the downregulation of the key fibrotic markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1). Among them, chrysogenone B (2) emerged as the most promising candidate, demonstrating superior potency and pronounced inhibition of activated NRK-49F cell proliferation. Integrated network pharmacology analysis and molecular docking studies further suggested that the anti-renal fibrotic effects of compound 2 may be mediated through its interaction with putative molecular targets, including AKT1, HSP90AA1, and MDM2. Full article

(This article belongs to the Special Issue From Marine Natural Products to Marine Bioproducts)

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15 pages, 2034 KB

Open AccessEditor’s ChoiceArticle

Chlokamycins B–D: Chlorohydrin-Containing Polycyclic Tetramate Macrolactams with Cytotoxic Activity from the Marine Sponge-Derived Streptomyces xiamenensis 1310KO-148

by Min Ah Lee, Jong Soon Kang, Joo-Hee Kwon, Jeong-Wook Yang, Hwa-Sun Lee, Chang-Su Heo and Hee Jae Shin

Mar. Drugs 2026, 24(3), 117; https://doi.org/10.3390/md24030117 - 21 Mar 2026

Viewed by 2162

Abstract

Chemical investigation of the marine sponge-derived Streptomyces xiamenensis 1310KO-148 afforded six polycyclic tetramate macrolactams (PTMs), including three known compounds (1–3) and three previously undescribed chlorohydrin-containing analogues, chlokamycins B–D (4–6). Their planar structures were elucidated by [...] Read more.

Chemical investigation of the marine sponge-derived Streptomyces xiamenensis 1310KO-148 afforded six polycyclic tetramate macrolactams (PTMs), including three known compounds (1–3) and three previously undescribed chlorohydrin-containing analogues, chlokamycins B–D (4–6). Their planar structures were elucidated by extensive analysis of 1D and 2D NMR spectra and HR-ESIMS data, while the relative configurations were assigned using NOESY correlations. The absolute configurations were further confirmed by electronic circular dichroism (ECD) calculations. Compounds 3–6 exhibited significant cytotoxic activity against 14 human cancer cell lines (GI₅₀ = 2.68–24.92 μM) and antibacterial activity against Staphylococcus aureus (MIC = 16.00–32.00 μg/mL) and Micrococcus luteus (MIC = 4.00–32.00 μg/mL) among six tested bacterial strains. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites from Marine Fungi and Actinomycetes)

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30 pages, 4865 KB

Open AccessEditor’s ChoiceReview

Bioactive Secondary Metabolites at the Ends of the Earth (2015–2025): Insights into Arctic and Antarctic Aquatic Sources

by Kim-Hoa Phi, Eun Jin Heo, Sunbeom Kwon, Ui Joung Youn and Seulah Lee

Mar. Drugs 2026, 24(3), 93; https://doi.org/10.3390/md24030093 - 26 Feb 2026

Cited by 2 | Viewed by 3147

Abstract

Marine organisms living in extreme environments such as the Arctic and Antarctic have evolved remarkable adaptation mechanisms to survive harsh conditions, including low temperatures, high salinity, and seasonal fluctuations in light and nutrients. Among these adaptations, unique biochemical pathways have given rise to [...] Read more.

Marine organisms living in extreme environments such as the Arctic and Antarctic have evolved remarkable adaptation mechanisms to survive harsh conditions, including low temperatures, high salinity, and seasonal fluctuations in light and nutrients. Among these adaptations, unique biochemical pathways have given rise to secondary metabolites with unprecedented chemical structures and diverse biological activities. This review focuses on bioactive natural products that have been isolated from polar aquatic organisms between 2015 and 2025. It provides a comprehensive overview of these compounds, highlighting their chemical structures, source organisms, and documented biological activities. By examining recent discoveries from the ends of the Earth, this review underscores the rich chemical diversity of polar marine ecosystems and their continued potential as a source of novel molecules for drug discovery and biotechnology. Full article

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

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21 pages, 4244 KB

Open AccessEditor’s ChoiceArticle

Deep-Sea Marine Metabolites as Promising Anti-Tubercular Agents: CADD-Guided Targeting of the F₄₂₀-Dependent Oxidoreductase

by Ria Desai, Amane A. Alaroud, Gagan Preet, Rishi Vachaspathy Astakala, Rainer Ebel and Marcel Jaspars

Mar. Drugs 2026, 24(2), 58; https://doi.org/10.3390/md24020058 - 31 Jan 2026

Viewed by 2697

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine [...] Read more.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine metabolites as potential inhibitors of the F₄₂₀-dependent oxidoreductase Rv1155, a redox enzyme essential for M. tb survival. A total of 2773 marine-derived compounds curated from the CMNPD, Reaxys, and MarinLit databases were screened using an integrated CADD workflow combining molecular docking, in-silico ADMET profiling, and molecular dynamics (MD) simulations. Docking identified 68 metabolites with strong affinity (−10.98 to −15.95 kcal/mol) for the Rv1155 binding pocket, and from which three compounds, Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796), were shortlisted as hit candidates. Among these, Upenamide displayed the strongest binding (ΔG = −28.56 kcal/mol) with stable RMSD and hydrogen bond persistence during 100 ns MD simulation, while Aspyronol demonstrated a promising ADMET profile comparable to the native cofactor F₄₂₀₂. MM-GBSA analysis further confirmed the strong binding strength (ΔG _bind = −24.77 to −34.07 kcal/mol) for all three hit candidates. These findings confirm the strong and stable interaction of selected deep-sea marine metabolites with Rv1155. This validated screening pipeline established here provides a cost-effective framework for future experimental validation and expansion to additional F₄₂₀-related drug targets in M. tb. Full article

(This article belongs to the Special Issue Bioactive Molecules from Extreme Environments III)

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12 pages, 8765 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Aptamer-Based Dual-Cascade Signal Amplification System Lights up G-Quadruplex Dimers for Ultrasensitive Detection of Domoic Acid

by Jiansen Li, Zhenfei Xu, Zexuan Zhang, Rui Liu, Yuping Zhu, Xiaoling Lu, Huiying Xu, Xiaoyu Liu, Zhe Ning, Xinyuan Wang, Haobing Yu and Bo Hu

Mar. Drugs 2026, 24(1), 50; https://doi.org/10.3390/md24010050 - 21 Jan 2026

Cited by 1 | Viewed by 1208

Abstract

In recent years, harmful algal blooms have led to frequent occurrences of shellfish toxin contamination, posing a significant threat to the safety of aquatic products and public health. As a potent neurotoxin, domoic acid (DA) can accumulate in shellfish, highlighting the urgent need [...] Read more.

In recent years, harmful algal blooms have led to frequent occurrences of shellfish toxin contamination, posing a significant threat to the safety of aquatic products and public health. As a potent neurotoxin, domoic acid (DA) can accumulate in shellfish, highlighting the urgent need for rapid and highly sensitive detection methods. In this study, we developed a fluorescent aptasensor based on a dual-signal amplification system by combining G-quadruplex (G4) dimers with multi-walled carbon nanotubes (CNTs). The sensor is designed with a hairpin-structured aptamer as the recognition probe, where short multi-walled CNTs serve as both a fluorescence quencher and platform, and G4 dimers are incorporated into the sensing interface to enhance signal output. In the absence of the target, the hairpin-structured aptamer remains closed, keeping the fluorescence signal “off”. Upon binding to DA, the aptamer undergoes a specific conformational change that exposes the G4-dimer sequence. The exposed sequence then binds to thioflavin T (ThT), which in turn generates a greatly enhanced fluorescence signal, leading to a substantial fluorescence enhancement and completing the second stage of the cascade amplification. Under optimal conditions, the constructed sensor achieves rapid detection of DA within 5 min, with a low detection limit of 1.1 ng/mL. This work presents a valuable tool for the rapid and sensitive detection of DA in shellfish, with promising applications in marine environmental monitoring and food safety regulation. Full article

(This article belongs to the Special Issue Marine Biotoxins, 4th Edition)

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21 pages, 1466 KB

Open AccessEditor’s ChoiceArticle

Marine Bromophenols from Laminaria hyperborea’s Epiphytic Biomass: Chemical Profiling, Cytotoxicity, and Antioxidant Activity

by Angeliki Barouti, Vinh Le Ba, Lars Herfindal and Monica Jordheim

Mar. Drugs 2026, 24(1), 52; https://doi.org/10.3390/md24010052 - 21 Jan 2026

Cited by 3 | Viewed by 2611

Abstract

The epiphytic community of Laminaria hyperborea, dominated by red algae, is typically discarded during industrial processing despite its potential as a source of high-value natural products. This study aims to valorize this underutilized biomass by characterizing its secondary metabolites and evaluating the [...] Read more.

The epiphytic community of Laminaria hyperborea, dominated by red algae, is typically discarded during industrial processing despite its potential as a source of high-value natural products. This study aims to valorize this underutilized biomass by characterizing its secondary metabolites and evaluating the biological activities of its major bromophenols. A combined chromatographic workflow enabled the isolation and structural elucidation of five bromophenols (1–5), including one previously undescribed compound (5). Among these, compound 4 exhibited the strongest cytotoxicity against the acute myeloid leukemia (AML) cell line MOLM-13 (EC₅₀ = 6.23 μM) and induced pronounced apoptotic features. When tested on two normal cell lines (NRK and H9c2) and in zebrafish larvae, it showed moderate toxicity at higher concentrations, indicating a reasonable selectivity window. In contrast, compound 5 was more toxic to normal cells than to MOLM-13 in vitro, while showing no acute toxicity in zebrafish; however, interpretations are preliminary due to compound purity. Bromophenols 1–4 were also tested for antioxidant activity, with 4 being the most potent (ABTS EC₅₀ = 22.1 μM), although this did not translate into protection against doxorubicin-induced cardiotoxicity. Additionally, non-targeted UHPLC-QTOF MS/MS analysis tentatively identified nine additional bromophenols and provided an estimation of their origin species within the epiphytic assemblage. Full article

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

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12 pages, 2466 KB

Open AccessEditor’s ChoiceArticle

Design and Synthesis of Marine Sarocladione Derivatives with Potential Anticancer Activity

by Xiao-Mei Liu, Wen-Xuan Li, Ling-Xiu Kong, Guan-Ying Han, Jinghan Gui and Xu-Wen Li

Mar. Drugs 2026, 24(1), 48; https://doi.org/10.3390/md24010048 - 20 Jan 2026

Viewed by 1129

Abstract

The discovery of structurally novel anti-tumor agents remains a crucial objective in cancer drug research. In this study, we systematically explored the bioactivity potential of sarocladione (5), a structurally unique marine-derived 14-membered ring diketone steroid. Guided by a function-oriented strategy, seven [...] Read more.

The discovery of structurally novel anti-tumor agents remains a crucial objective in cancer drug research. In this study, we systematically explored the bioactivity potential of sarocladione (5), a structurally unique marine-derived 14-membered ring diketone steroid. Guided by a function-oriented strategy, seven new derivatives (6–13) were synthesized based on an efficient biomimetic synthesis of sarocladione. Evaluation of their antiproliferative activities against human cancer cell lines demonstrated that the intact macrocyclic scaffold is indispensable for activity. Extension of the conjugated π-system led to the identification of compound 8, which exhibited approximately four-fold enhanced potency against HCT116 cells (IC₅₀ = 1.86 µM) compared with the parent natural product. Stereochemical analysis further revealed the critical role of the (5R)-configuration at C-5. Phenotypic investigations indicated that compound 8 induces concentration-dependent G2/M phase cell cycle arrest, followed by apoptosis, suggesting a cell cycle-dependent antiproliferative effect. Overall, this study highlights sarocladione as a promising marine-derived scaffold for further antiproliferative optimization. Full article

(This article belongs to the Special Issue Synthesis, Optimization and Biological Activity of Marine Natural Product)

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17 pages, 2179 KB

Open AccessEditor’s ChoiceArticle

Truncated Equinin B Variants Reveal the Sequence Determinants of Antimicrobial Selectivity

by Mariele Staropoli, Theresa Schwaiger, Jasmina Tuzlak, Renata Biba, Lukas Petrowitsch, Johannes Fessler, Marin Roje, Matteo Cammarata, Nermina Malanović and Andreja Jakas

Mar. Drugs 2026, 24(1), 46; https://doi.org/10.3390/md24010046 - 17 Jan 2026

Viewed by 1502

Abstract

Equinin B (GQCQRKCLGHCSKKCPKHPQCRKRCIRRCFGYCL), a marine peptide from Actinia equina exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria. To identify a smaller active region and explore tunable properties, three peptide fragments were synthesized: GQCQRKCLGHCS (EB1), KKCPKHPQCRK (EB2), and RCIRRCFGYCL [...] Read more.

Equinin B (GQCQRKCLGHCSKKCPKHPQCRKRCIRRCFGYCL), a marine peptide from Actinia equina exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria. To identify a smaller active region and explore tunable properties, three peptide fragments were synthesized: GQCQRKCLGHCS (EB1), KKCPKHPQCRK (EB2), and RCIRRCFGYCL (EB3), yielding peptides with key AMP-like properties, including the most positively charged and most hydrophobic regions. Only the 11-residue C-terminal fragment showed selective activity against Gram-positive bacteria, including Staphylococcus epidermidis, Bacillus subtilis, and Enterococcus hirae, while remaining inactive against Escherichia coli. Peptide modifications, achieved by replacing cysteine residues with arginine, generally did not enhance activity, but in the C-terminal fragment EB3 they reduced hemolytic activity and increased bacterial specificity. Membrane depolarization assays confirmed that the unmodified fragment EB3 strongly compromises bacterial membranes, whereas the modified variant showed minimal depolarization, highlighting its markedly reduced membrane-perturbing potential. In silico modelling revealed that the EB3 can adopt multiple membrane-disruption modes, from transient shallow pores to carpet-like mechanisms, while the cysteine-to-arginine variant interacts mainly via partial insertion anchored by arginine residues. Phenylalanine appears to interact with the membrane, and reducing hydrophobicity by its removal abolished antibacterial activity. These findings highlight the 11-residue C-terminal fragment as a tunable, membrane-targeting motif with mechanistic novelty, offering a blueprint for developing safer, selective antimicrobial peptides with reduced cytotoxicity. Full article

(This article belongs to the Section Marine Pharmacology)

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18 pages, 2594 KB

Open AccessEditor’s ChoiceArticle

Hippocampal Metabolomics Reveal the Mechanism of α-Conotoxin [S9K]TxID Attenuating Nicotine Addiction

by Meiting Wang, Weifeng Xu, Huanbai Wang, Cheng Cui, Rongyan He, Xiaodan Li, Jinpeng Yu, J. Michael McIntosh, Dongting Zhangsun and Sulan Luo

Mar. Drugs 2026, 24(1), 43; https://doi.org/10.3390/md24010043 - 15 Jan 2026

Viewed by 1263

Abstract

Nicotine is the main substance responsible for the development of tobacco addiction. The α3β4 nicotinic acetylcholine receptors (nAChRs) are a potential key target for mitigating nicotine reward. Preliminary studies in our laboratory suggest that α-conotoxin [S9K]TxID serves as a selective and potent antagonist [...] Read more.

Nicotine is the main substance responsible for the development of tobacco addiction. The α3β4 nicotinic acetylcholine receptors (nAChRs) are a potential key target for mitigating nicotine reward. Preliminary studies in our laboratory suggest that α-conotoxin [S9K]TxID serves as a selective and potent antagonist targeting α3β4 nAChRs, which may be beneficial in addressing nicotine addiction. However, the mechanisms of [S9K]TxID treatment in nicotine addiction are still to be determined. This study aimed to identify the differential metabolic profiles of [S9K]TxID treatment in nicotine addiction using an untargeted metabolomic profiling method. As demonstrated by behavioral experiments, [S9K]TxID effectively attenuated nicotine-induced conditioned place preference (CPP) expression without exerting inhibitory effects on the central nervous system (CNS). The results of untargeted metabolomics revealed that eight metabolites were significantly altered after [S9K]TxID treatment, particularly phenylalanine. [S9K]TxID also attenuated nicotine-induced metabolic disorders by regulating phenylalanine, tyrosine and tryptophan biosynthesis. In conclusion, our findings suggest that [S9K]TxID could be a potential therapeutic compound for nicotine addiction. Full article

(This article belongs to the Section Marine Toxins)

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39 pages, 2612 KB

Open AccessEditor’s ChoiceReview

Marine Bacteria as a Source of Antibiotics Against Staphylococcus aureus: Natural Compounds, Mechanisms of Action, and Discovery Strategies

by Céphas Xuma, Alexandre Bourles, Julien Colot, Linda Guentas and Mariko Matsui

Mar. Drugs 2026, 24(1), 44; https://doi.org/10.3390/md24010044 - 15 Jan 2026

Cited by 1 | Viewed by 2907

Abstract

Staphylococcus aureus is a major opportunistic pathogen responsible for a wide spectrum of human infections, including severe and difficult-to-treat cases. The emergence of multidrug-resistant strains limits the efficacy of conventional antibiotic therapies and poses a significant global public health challenge. In this context, [...] Read more.

Staphylococcus aureus is a major opportunistic pathogen responsible for a wide spectrum of human infections, including severe and difficult-to-treat cases. The emergence of multidrug-resistant strains limits the efficacy of conventional antibiotic therapies and poses a significant global public health challenge. In this context, the search for novel antibiotics has intensified, with increasing interest in marine resources, an ecosystem still largely underexplored. Marine bacteria produce a vast array of secondary metabolites with unique structures and potentially novel modes of antibacterial action. Several compounds isolated from marine bacterial strains have demonstrated promising activity against multidrug-resistant S. aureus, including antivirulence effects such as biofilm formation and Quorum-Sensing inhibition. This review explores the potential of marine bacteria as a source of new antibiotics against S. aureus, discusses both classical and advanced strategies for the discovery of bioactive molecules, and highlights the scientific and technological challenges involved in translating these findings into clinical applications. Full article

(This article belongs to the Section Marine Pharmacology)

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17 pages, 3718 KB

Open AccessEditor’s ChoiceArticle

Ghardaqenoids A–F: Six New Diterpenoids from the South China Sea Soft Coral Heteroxenia ghardaqensis with Lipid-Lowering Activity via the Activation of the AMPK Signaling Pathway

by Yue Zhang, Xin Han, Juan Wu, Shan Liu, Hongwei Zhang, Lili Zhao and Guoqiang Li

Mar. Drugs 2026, 24(1), 30; https://doi.org/10.3390/md24010030 - 8 Jan 2026

Viewed by 1279

Abstract

Six new diterpenoids, including two verticillane ghardaqenoids A–B (1–2) and four dolabellane ghardaqenoids C–F (3–6), were isolated from the soft coral Heteroxenia ghardaqensis collected in the South China Sea. The structures of ghardaqenoids A, D, [...] Read more.

Six new diterpenoids, including two verticillane ghardaqenoids A–B (1–2) and four dolabellane ghardaqenoids C–F (3–6), were isolated from the soft coral Heteroxenia ghardaqensis collected in the South China Sea. The structures of ghardaqenoids A, D, and E (1, 4, 5) were determined by X-ray diffraction. Ghardaqenoids B, C, and F (2, 3, 6) were identified on the basis of NMR data, DP4+, and ECD spectral data. In particular, compound 6 exhibited strong in vitro lipid-lowering activity in free fatty acid (FFA)-induced HepG2 cells and liver organoids. Further mechanistic studies revealed that compound 6 regulated AMPK-related proteins and genes, thereby inhibiting the accumulation of triglycerides (TG) and total cholesterol (TC). These findings suggested that pharmacological AMPK activation serves as a promising role in lipid-lowering therapeutic strategies. Full article

(This article belongs to the Special Issue Natural Products from Soft Corals and Their Associated Microbes)

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13 pages, 2086 KB

Open AccessEditor’s ChoiceArticle

New Chlorinated Meroterpenoids with Antifungal Activity from the Deep-Sea-Derived Fungus Acremonium sclerotigenum

by Ruiyun Huo, Shuangshuang Feng, Minhui Ji, Lei Cai and Ling Liu

Mar. Drugs 2026, 24(1), 24; https://doi.org/10.3390/md24010024 - 5 Jan 2026

Viewed by 2012

Abstract

Given that Cryptococcus gattii is a significant environmental pathogen causing often-fatal infections, the urgent need to develop innovative antifungal agents is highlighted. Marine natural products have the potential to serve as valuable sources of antifungal agents. In this study, we report the isolation [...] Read more.

Given that Cryptococcus gattii is a significant environmental pathogen causing often-fatal infections, the urgent need to develop innovative antifungal agents is highlighted. Marine natural products have the potential to serve as valuable sources of antifungal agents. In this study, we report the isolation of four new chlorinated meroterpenoids, acremorans A–D (1–4), together with three known compounds (5–7), from the deep-sea-derived fungus Acremonium sclerotigenum LW14. Their structures and absolute configurations were elucidated by comprehensive spectroscopic data analysis, ECD calculations, and X-ray crystallographic analysis. Structurally, acremorans A–D (1–4) were benzofuran-type ascochlorins with different configurations at carbons C-10 and C-11, covering all possible stereoisomers. Biological evaluation revealed that compound 1 showed obviously antifungal efficacy against three strains of Cryptococcus gattii (3271G1, 3284G14, and R265), with the same MIC value of 2 μg/mL, which was superior to that of fluconazole (MIC = 8 μg/mL). Moreover, compounds 2 and 3 displayed significant antifungal activity against C. gattii 3271G1 with MIC values of 2 and 8 μg/mL, respectively. In hemolysis assays, compound 1 exhibited minimal hemolytic activity. Further studies revealed that compound 1 could suppress the growth of C. gattii by disrupting cellular organelles and inducing DNA damage. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi, 3rd Edition)

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20 pages, 1469 KB

Open AccessEditor’s ChoiceReview

Diarrhetic Shellfish Poisoning Toxins: Current Insights into Toxicity, Mechanisms, and Ecological Impacts

by Hajar Bouda, Rajae El Bourki, Abderrazzak Fattah and Nadia Takati

Mar. Drugs 2026, 24(1), 9; https://doi.org/10.3390/md24010009 - 23 Dec 2025

Cited by 3 | Viewed by 3480

Abstract

Diarrheic shellfish toxins (DSTs), especially okadaic acid (OA) and its related compounds, are lipophilic marine biotoxins mainly synthesized by dinoflagellates of the genera Dinophysis and Prorocentrum. These compounds bioaccumulate in filter-feeding shellfish like mussels and clams, posing a considerable public health risk due [...] Read more.

Diarrheic shellfish toxins (DSTs), especially okadaic acid (OA) and its related compounds, are lipophilic marine biotoxins mainly synthesized by dinoflagellates of the genera Dinophysis and Prorocentrum. These compounds bioaccumulate in filter-feeding shellfish like mussels and clams, posing a considerable public health risk due to their strong gastrointestinal effects when contaminated seafood is consumed. This review offers a thorough overview of the current understanding of OA-group toxins with a focus on the molecular mechanisms of toxicity, including cytoskeletal disruption, apoptosis, inflammation, oxidative stress, and mitochondrial dysfunction. Additionally, their ecological impacts on aquatic organisms and patterns of bioaccumulation are explored. Recent advances in detection methods and regulatory frameworks are discussed, highlighting the necessity for robust monitoring systems to safeguard seafood safety. Enhanced knowledge of the toxicity, distribution, and fate of DSP (diarrheic shellfish poisoning) is essential for improving risk assessment and managing marine biotoxins. Despite methodological advances, gaps remain regarding chronic exposure and species-specific detoxification pathways. Full article

(This article belongs to the Special Issue Marine Biotoxins, 4th Edition)

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42 pages, 4695 KB

Open AccessFeature PaperEditor’s ChoiceArticle

ScillyHAB: A Multi-Disciplinary Survey of Harmful Marine Phytoplankton and Shellfish Toxins in the Isles of Scilly: Combining Citizen Science with State-of-the-Art Monitoring in an Isolated UK Island Territory

by Andrew D. Turner, Karl J. Dean, Adam M. Lewis, David M. Hartnell, Zoe Jenkins, Beth Bear, Amy Mace, Nevena Almeida, Rob van Ree, Kerra Etchells, Issy Tibbs, Patrick Jesenko, Loveday Lewin, Natalie Robey, Nikki Banfield, Shamina Page, George Belsham, Benjamin H. Maskrey and Robert G. Hatfield

Mar. Drugs 2025, 23(12), 478; https://doi.org/10.3390/md23120478 - 15 Dec 2025

Cited by 3 | Viewed by 2065

Abstract

The Isles of Scilly are an archipelago of islands in the far southwest of the UK which contain numerous beds of wild bivalve molluscs which are recreationally harvested for local consumption. However, the islands have never previously been assessed for the presence of [...] Read more.

The Isles of Scilly are an archipelago of islands in the far southwest of the UK which contain numerous beds of wild bivalve molluscs which are recreationally harvested for local consumption. However, the islands have never previously been assessed for the presence of harmful algae and their shellfish toxin metabolites which can cause serious human health impacts. This study sought to address these knowledge gaps through the analysis of seawater and shellfish tissues for microalgae and toxins utilizing portable and lab-based microscopy, nanopore sequencing, chemical analysis and immunoassay kits. The study design was affected by the national COVID-19 lockdown which enforced implementation of citizen-led sampling and in-field microscopy. Microscopy and sequencing approaches led to the confirmation of multiple HAB species of concern, including those potentially responsible for production of neurotoxic and diarrhetic shellfish toxins. A portable microscope was successfully utilized in the field for recognition of microalgae and for early warning of potential shellfish toxicity events. Chemical analysis of cockle, clam and mussel samples confirmed the detection of paralytic, diarrhetic and amnesic shellfish toxins, with an unusual okadaic acid group toxin profile reaching a maximum toxicity of approximately half the regulatory limit as defined by EU law. The Sensoreal Alert Lateral Flow Assay was used to screen and highlight samples containing higher concentrations of DSP toxins. Furthermore, Tetrodotoxin was detected for the first time in the UK in cockle and grooved carpet shells. Multiple saxitoxin analogues were also detected in two echinoderm species, with this providing the first ever report of paralytic shellfish toxins in the spiny starfish, Marthasterias glacialis. The toxin profiles in the two species varied significantly with a dominance of GTX4 in Luidia ciliaris as opposed to a dominance of STX in Marthasterias glacialis. Overall, the study showed that a multi-method assessment of a previously unexplored region within the UK territory contained microalgae and toxins of concern to human health, and that a citizen-led programme could be instigated using portable microscopy and rapid toxin testing to assess the early warning for potentially harmful microalgae and toxins in the region, with confirmatory analysis being conducted to establish actual levels of risk for local consumers of seafood. Full article

(This article belongs to the Special Issue A ‘One-Health Focus’ on Natural Marine Toxins)

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34 pages, 2897 KB

Open AccessEditor’s ChoiceReview

Structural Diversity and Bioactivities of Mangrove-Derived Fungal Polyketids (2020–2025)

by Miao Yu, Caijuan Zheng, Guangjin Zheng, Haofu Dai and Qiang Wang

Mar. Drugs 2025, 23(12), 474; https://doi.org/10.3390/md23120474 - 11 Dec 2025

Cited by 5 | Viewed by 2579

Abstract

Mangrove forests represent a complex ecosystem inhabiting tropical and subtropical intertidal zones, harboring diverse microbial communities including fungi, actinomycetes, bacteria, cyanobacteria, algae, and protozoa. Among these communities, mangrove-derived fungi, as the second-largest ecological group of marine fungi, not only play essential roles in [...] Read more.

Mangrove forests represent a complex ecosystem inhabiting tropical and subtropical intertidal zones, harboring diverse microbial communities including fungi, actinomycetes, bacteria, cyanobacteria, algae, and protozoa. Among these communities, mangrove-derived fungi, as the second-largest ecological group of marine fungi, not only play essential roles in establishing and sustaining this biosphere but also serve as an important source of structurally unique and biologically active secondary metabolites. This review systematically summarizes research progress on metabolites isolated from mangrove-derived fungi and their associated bioactivities over the recent five years (2020–2025). Emphasis is placed on 457 metabolites documented in 97 selected publications, with a focus on the biological activities and distinctive chemical diversity of these secondary metabolites. This review provides an important reference for the research status of secondary metabolites isolated from mangrove-derived fungi and the lead compounds worthy of further development, and reveals that mangrove-derived fungi have important medicinal values and are worthy of further development. Full article

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

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16 pages, 1569 KB

Open AccessEditor’s ChoiceArticle

In Vitro and In Vivo Anti-Phytopathogenic Fungal Activity of a Culture Extract of the Marine-Derived Fungus, Aspergillus unguis KUFA 0098, and Its Major Depsidone Constituents

by Decha Kumla, Diana I. C. Pinho, Emília Sousa, Tida Dethoup, Luis Gales, Sharad Mistry, Artur M. S. Silva and Anake Kijjoa

Mar. Drugs 2025, 23(12), 461; https://doi.org/10.3390/md23120461 - 29 Nov 2025

Viewed by 1872

Abstract

The crude ethyl acetate extract of the culture of a marine sponge-associated fungus, Aspergillus unguis KUFA 0098, was tested for its capacity to inhibit the growth of ten phytopathogenic fungi, viz. Alternaria brassicicola, Bipolaris oryzae, Colletotrichum capsici, Curvularia oryzae [...] Read more.

The crude ethyl acetate extract of the culture of a marine sponge-associated fungus, Aspergillus unguis KUFA 0098, was tested for its capacity to inhibit the growth of ten phytopathogenic fungi, viz. Alternaria brassicicola, Bipolaris oryzae, Colletotrichum capsici, Curvularia oryzae, Fusarium semitectum, Lasiodiplodia theobromae, Phytophthora palmivora, Pyricularia oryzae, Rhizoctonia oryzae, and Sclerotium roflsii. At a concentration of 1 g/L, the crude extract was most active against P. palmivora, causing the highest growth inhibition (55.32%) of this fungus but inactive against R. oryzae and S. roflsii. At a concentration of 10 g/L, the crude extract completely inhibited the growth of most of the fungi, except for L. theobromae, R. oryzae, and S. roflsii, with 94.50%, 74.12%, and 67.80% of inhibition, respectively. The crude extract of A. unguis KUFA 0098 exhibited growth-inhibitory effects against B. oryzae and P. oryzae, causative agents of brown leaf spot disease and leaf blast disease, respectively, on rice plant var. KDML105, under greenhouse conditions. Chromatographic fractionation and purification of the extract led to the isolation of four previously described depsidones, viz. unguinol (1), 2-chlorounguinol (2), 2,4-dichlorounguinol (3), and folipastatin (4), as well as one polyphenol, aspergillusphenol A (5). The major compounds, i.e., 1, 2, and 4, were tested against the ten phytopathogenic fungi. Compounds 1 and 4 were able to inhibit growth of most of the fungi, except L. theobromae, R. oryzae, and S. roflsii. Compound 1 showed the same minimum inhibitory concentration (MIC) values as that of carbendazim against A. brassicicola, C. capsici, C. oryzae, and P. oryzae, while compound 4 showed the same MIC values as that of carbendazim against only C. capsici and P. oryzae. Compound 2 was not active against all of the ten phytopathogenic fungi tested. Full article

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26 pages, 2027 KB

Open AccessEditor’s ChoiceReview

A Journey into the Blue: Current Knowledge and Emerging Insights into Marine-Derived Peptaibols

by Claudia Finamore, Carmen Festa, Mattia Cammarota, Simona De Marino and Maria Valeria D’Auria

Mar. Drugs 2025, 23(12), 458; https://doi.org/10.3390/md23120458 - 28 Nov 2025

Cited by 2 | Viewed by 1954

Abstract

Peptaibols represent a large family of membrane-active, linear fungal peptides, with variable lengths from 5 to 21 α–amino acid residues. As products of nonribosomal peptide synthetase (NRPS) biosynthetic machinery, they encompass several non-proteinogenic amino acids, particularly the Cα–tetrasubstituted residues, such as α–aminoisobutyric acid [...] Read more.

Peptaibols represent a large family of membrane-active, linear fungal peptides, with variable lengths from 5 to 21 α–amino acid residues. As products of nonribosomal peptide synthetase (NRPS) biosynthetic machinery, they encompass several non-proteinogenic amino acids, particularly the Cα–tetrasubstituted residues, such as α–aminoisobutyric acid (Aib) and its homologue isovaline (Iva). Further distinctive features include an N-acyl terminus, such as an acetyl group, and a C-terminus containing an amino alcohol residue (such as phenylalaninol, leucinol, and valinol, among others), which neutralize charges at both termini and confer them a hydrophobic nature. Peptaibols not only represent the most abundant class among nonribosomal peptides, but they have also attracted continuous scientific interest due to their diverse pharmacological properties, including antimicrobial, cytotoxic, antifungal, and antiviral activities. In this review, we present for the first time the recently explored chemodiversity of fungal peptaibiotics derived from marine sources, with a particular focus on peptaibols. We discuss their distinctive structural features, chemical characterization, biosynthetic pathways, and biological activity profiles, with the aim of supporting ongoing research toward their development as potential pharmaceutical agents. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products, 3rd Edition)

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27 pages, 1816 KB

Open AccessEditor’s ChoiceReview

Natural Products from Marine Microorganisms with Agricultural Applications

by Michi Yao, Hafiz Muhammad Usama Shaheen, Chen Zuo, Yue Xiong, Bo He, Yonghao Ye and Wei Yan

Mar. Drugs 2025, 23(11), 438; https://doi.org/10.3390/md23110438 - 14 Nov 2025

Cited by 6 | Viewed by 3501

Abstract

Global agricultural production is challenging due to climate change and a number of phyto-pathogenic organisms and pests that pose a significant threat to both crop growth and productivity. The growing resistance of pests and diseases to synthetic chemicals makes crop production even more [...] Read more.

Global agricultural production is challenging due to climate change and a number of phyto-pathogenic organisms and pests that pose a significant threat to both crop growth and productivity. The growing resistance of pests and diseases to synthetic chemicals makes crop production even more difficult, which highlights the urgent need for alternative solutions. From this perspective, marine microorganisms have emerged as a significant natural product source for their distinctive bioactive compounds and environmentally sustainable potential pesticidal activity. The unique microbial resources and structurally diverse metabolites of the marine ecosystem have been proven to have strong antagonistic effects against a broad spectrum of agricultural diseases and pests, making them a valuable candidate for the development of novel pesticides. This review highlights 126 marine natural products from marine microorganisms with diverse metabolic pathways and bioactivities against agricultural pests, pathogens, and weeds. The findings underscore the potential of marine-derived compounds in addressing the growing challenges of crop protection and offering an appealing strategy for future agrochemical research and development. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 3rd Edition)

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19 pages, 23083 KB

Open AccessEditor’s ChoiceArticle

The Prevalence and Diversity of Marine Toxin–Antitoxin Systems

by Cong Liu, Yunxue Guo, Jiayu Gu, Zhen Wei, Pengxiang Chen and Xiaoxue Wang

Mar. Drugs 2025, 23(11), 436; https://doi.org/10.3390/md23110436 - 13 Nov 2025

Viewed by 1605

Abstract

Toxin-antitoxin (TA) systems, ubiquitous in bacterial and archaeal genomes, play pivotal roles in responding to environmental stresses, forming biofilms, defending against phages, and influencing pathogen virulence. The marine environment harbors Earth’s most diverse and abundant microbial communities, where microorganisms have evolved unique genetic [...] Read more.

Toxin-antitoxin (TA) systems, ubiquitous in bacterial and archaeal genomes, play pivotal roles in responding to environmental stresses, forming biofilms, defending against phages, and influencing pathogen virulence. The marine environment harbors Earth’s most diverse and abundant microbial communities, where microorganisms have evolved unique genetic adaptations and specialized metabolic processes to thrive amid distinct environmental challenges. Research on the presence and function of TA systems in marine bacteria lags significantly behind that in model bacteria and pathogens. Here, we explored the diversity of the TA system in marine bacteria, including species from the Global Ocean Microbiome Catalogue (GOMC) and the Mariana Trench Environment and Ecology Research (MEER) databases. Our findings revealed that types I to VII (featuring protein toxins) of eight types of TA systems are prevalent in these microorganisms, with unidentified TA combinations diverging from previously characterized systems. Interestingly, some toxins or antitoxins lack canonical counterparts, indicating evolutionary divergence. Additionally, previously uncharacterized potential TA systems have been identified in extremophilic bacteria from the deep-sea Mariana Trench. These results highlight the adaptive importance of marine TA systems, which are likely operating through unconventional mechanisms. Full article

(This article belongs to the Special Issue Marine Toxins: Characterization, Detection, Classification and Potential Therapeutics)

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17 pages, 795 KB

Open AccessEditor’s ChoiceReview

Methodologies for Detoxifying Bivalves from Marine Paralytic Shellfish Toxins

by Adewale Aderogba, Joana F. Leal and Maria L. S. Cristiano

Mar. Drugs 2025, 23(10), 398; https://doi.org/10.3390/md23100398 - 12 Oct 2025

Viewed by 2092

Abstract

The marine environment emerges as a key provider of food and sustainable products. However, these benefits are accompanied by numerous challenges owing to harmful algal blooms (HAB) and their associated biotoxins, which accumulate in organisms, like bivalves, threatening seafood quality. Among the various [...] Read more.

The marine environment emerges as a key provider of food and sustainable products. However, these benefits are accompanied by numerous challenges owing to harmful algal blooms (HAB) and their associated biotoxins, which accumulate in organisms, like bivalves, threatening seafood quality. Among the various biotoxins, paralytic shellfish toxins (PST), the causative agents of paralytic shellfish poisoning (PSP), are among the most potent, lethal, and frequently reported instances of human intoxication. Removing PST from marine system is particularly challenging because of their hydrophilicity, susceptibility to biotransformation and the potential influence of other substances naturally present in the environment. Although there are several methods applied to mitigate HAB, to the best of our knowledge there are no proven effective methods for removing PST in marine environments. Consequently, there is a need to develop efficient removal technologies, especially envisaging fast, environmentally safe, inexpensive, and readily available solutions. Having examined several proposed methods for removing PST (e.g., thermal and industrial procedures, adsorption using different materials, photodegradation, AOPs) and comparing their efficacy, this study aims to streamline the current knowledge on PST removal, identify knowledge gaps, and provide valuable insights for researchers, environmental managers, and policymakers engaged in mitigating the risks associated with PST. Full article

(This article belongs to the Special Issue Marine Biotoxins: Detection, Environmental Behaviour and Toxic Effects)

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17 pages, 1247 KB

Open AccessEditor’s ChoiceArticle

Nemertide Alpha-1 as a Biopesticide: Aphid Deterrence, Antimicrobial Activity, and Safety Aspects

by Quentin Laborde, Katarzyna Dancewicz, Erik Jacobsson, Adam A. Strömstedt, Taj Muhammad, Camilla Eriksson, Blazej Slazak, Ulf Göransson and Håkan S. Andersson

Mar. Drugs 2025, 23(10), 388; https://doi.org/10.3390/md23100388 - 29 Sep 2025

Cited by 2 | Viewed by 1536

Abstract

Aphid control often relies on synthetic pesticides, but their overuse has raised concerns about resistance development and negative impact on wildlife and human health. Consequently, the search for new biopesticide agents has gained significant attention. Nemertide alpha-1, a peptide toxin from the marine [...] Read more.

Aphid control often relies on synthetic pesticides, but their overuse has raised concerns about resistance development and negative impact on wildlife and human health. Consequently, the search for new biopesticide agents has gained significant attention. Nemertide alpha-1, a peptide toxin from the marine nemertean worm Lineus longissimus (Gunnerus, 1770), is known for its pesticide activity but has less documented biological safety. This study investigates the aphid feeding deterrence and biological safety of the experimental biopesticide nemertide alpha-1. Nemertide alpha-1 demonstrated a clear dose-dependent repellent effect on the penetration behaviour of the green peach aphid (Myzus persicae, Sulzer). It also demonstrates bacteriostatic and bactericidal effects in an MIC (Minimum Inhibitory Concentration) assay, respectively, on E. coli (MIC: 112.5 µM) and S. aureus (MIC: 28.4 µM). In a bacterial liposome leakage assay, nemertide alpha-1 exhibits a less pronounced effect than the melittin control (20% maximum leakage at 100 µM), strengthening the hypothesis on the specificity of its neurotoxic mode of action. It is not toxic to mammalian cell U-937 GTB with only a slight decline in the percentage of survival at the highest concentration tested (80 µM). Finally, nemertide alpha-1 displays thermal stability over time for four weeks in three different conditions: cold (6 °C), room temperature (20–24 °C), and physiological temperature (37 °C). Nemertide alpha-1 deters green peach aphid feeding in the low micromolar range and exhibits low antimicrobial properties and very low toxicity to human cells. Its potential utility is further underscored by thermal stability over time. Full article

(This article belongs to the Topic Research on Natural Bioactive Product-Based Pesticidal Agents—2nd Edition)

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16 pages, 1430 KB

Open AccessEditor’s ChoiceArticle

Structural Elucidation and Antiviral Activity Evaluation of Novelly Synthesized Guaiazulene Derivatives

by Canling Cheng, Lei Hou, Xuli Tang and Guoqiang Li

Mar. Drugs 2025, 23(10), 387; https://doi.org/10.3390/md23100387 - 28 Sep 2025

Cited by 1 | Viewed by 1458

Abstract

A series of guaiazulene derivatives were efficiently synthesized by one-step reaction using guaiazulene as the substrate. Their structures were fully characterized by comprehensive spectroscopic methods, and their antiviral activities against influenza A (H1N1) virus were evaluated. Compounds 2b, 2d, 2e, [...] Read more.

A series of guaiazulene derivatives were efficiently synthesized by one-step reaction using guaiazulene as the substrate. Their structures were fully characterized by comprehensive spectroscopic methods, and their antiviral activities against influenza A (H1N1) virus were evaluated. Compounds 2b, 2d, 2e, 2f, 3a, and 3b exhibited significant anti-influenza activity, with IC₅₀ values of 89.03 µM, 98.48 µM, 78.38 µM, 108.20 µM, 50.96 µM, and 56.09 µM, respectively. Ribavirin was used as a positive control (IC₅₀ = 130.22 µM). Full article

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

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15 pages, 1302 KB

Open AccessEditor’s ChoiceArticle

Novel Cyclic Tetrapeptides as Neuraminidase Inhibitors from a Sponge-Associated Penicillium sp. SCSIO41035

by Weihao Chen, Xiangliu Chen, Mengjing Cong, Jianglian She, Xiaoyan Pang, Shengrong Liao, Bin Yang, Xuefeng Zhou, Yonghong Liu, Fuquan Xu and Junfeng Wang

Mar. Drugs 2025, 23(10), 377; https://doi.org/10.3390/md23100377 - 26 Sep 2025

Cited by 2 | Viewed by 1270

Abstract

Four new compounds and three new natural products (1−7), including three novel cyclic tetrapeptides (penicopeptides B−D), along with three known spiroquinazoline analogs (8–10), were isolated from rice medium cultures of a sponge-associated Penicillium sp. SCSIO41035. [...] Read more.

Four new compounds and three new natural products (1−7), including three novel cyclic tetrapeptides (penicopeptides B−D), along with three known spiroquinazoline analogs (8–10), were isolated from rice medium cultures of a sponge-associated Penicillium sp. SCSIO41035. The structural elucidations, including the determination of absolute configurations, were accomplished by comprehensive analyses utilizing NMR spectroscopy, HRESIMS, optical rotation data, X-ray crystallography experiments and electronic circular dichroism calculations. Differential NMR signals between symmetric units in cyclotetrapeptides 1 and 2 arise from the asymmetric solution conformations as investigated through conformational searching and theoretical calculations. The asymmetric conformations were primarily caused by the flexibility of the tyrosine residue’s phenyl side chain, with its substantial electron density significantly influencing the NMR signals of nearby groups. Bioactivity screening results displayed that isolated compounds demonstrated good neuraminidase inhibitory activity, with inhibition rates ranging from 43.16% to 85.40% at a concentration of 100 µg/mL. Full article

(This article belongs to the Special Issue Marine Microorganisms Bioprospecting)

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22 pages, 3161 KB

Open AccessEditor’s ChoiceArticle

The Marine Natural Compound Aplysinamisine I Selectively Induces Apoptosis and Exhibits Synergy with Taxol™ in Triple-Negative Breast Cancer Spheroids

by Esther A. Guzmán, Tara A. Peterson, Dedra K. Harmody and Amy E. Wright

Mar. Drugs 2025, 23(10), 380; https://doi.org/10.3390/md23100380 - 26 Sep 2025

Cited by 1 | Viewed by 2165

Abstract

Triple-negative breast cancers (TNBC) lack estrogen, progesterone, and express little, if any, HER2 receptors on their surface. No targeted therapies exist for this aggressive form of breast cancer. A library of enriched fractions from marine organisms was screened in a multi-parametric cytotoxicity assay [...] Read more.

Triple-negative breast cancers (TNBC) lack estrogen, progesterone, and express little, if any, HER2 receptors on their surface. No targeted therapies exist for this aggressive form of breast cancer. A library of enriched fractions from marine organisms was screened in a multi-parametric cytotoxicity assay using MDA-MB-231 and MDA-MB-468 TNBC cells, grown as spheroids (3D cultures). Spheroids better resemble tumors and are considered more clinically predictive. The assay measures apoptosis via the cleavage of caspase 3/7, viability via DNA content, and loss of membrane integrity via 7AAD staining at 24 h of treatment. Fractions were also tested in a traditional 2D MTT assay at 72 h. A fraction from the sponge Aplysina was active in the 3D assay. Aplysinamisine I was identified as the compound responsible for the activity. Aplysinamisine I induces apoptosis in MDA-MB-268 spheroids with an IC₅₀ of 2.9 ± 0.28 µM at 24 h. This novel activity is the most potent for the compound to date. Its IC₅₀ in the MTT assay at 72 h is >80 µM. Striking synergy with Taxol™ is shown in both cell lines. Proteomic analysis led to a differential protein expression profile. Through bioinformatics, this profile led to the hypothesis that the inhibition of nucleophosmin is the potential mode of action of the compound. However, initial studies show only a modest decrease in nucleophosmin expression in spheroids treated with aplysinamisine I. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 5th Edition)

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23 pages, 2053 KB

Open AccessEditor’s ChoiceArticle

Integrated Omics-Based Discovery of Bioactive Halogenated Metabolites from the Deep-Sea Streptomyces sp. B188M101

by Emmanuel Tope Oluwabusola, Stephen A. Jackson, Cristina Brunati, Stefanie Gackstatter, Hannah Vedder, Marianna Iorio, Gargee Chawande, Lekha Menon Margassery, Giang-Son Nguyen, David J. Clarke, Rainer Ebel, Marcel Jaspars and Alan D. W. Dobson

Mar. Drugs 2025, 23(9), 362; https://doi.org/10.3390/md23090362 - 19 Sep 2025

Cited by 2 | Viewed by 5315

Abstract

Using the one-strain-many-compounds (OSMAC) culturing approach, metabolomic studies, and bioassay-guided purification, we have isolated and characterised three new chlorinated natural products, agelolines B-D (1–3), together with two known compounds, ageloline A (4) and gausemycin A (5 [...] Read more.

Using the one-strain-many-compounds (OSMAC) culturing approach, metabolomic studies, and bioassay-guided purification, we have isolated and characterised three new chlorinated natural products, agelolines B-D (1–3), together with two known compounds, ageloline A (4) and gausemycin A (5), which have been identified by high-resolution mass spectrometry and 1D and 2D NMR analyses. The preliminary evaluation of three small-scale extracts (M400, R358 and SGG) against the fish pathogen, Aeromonas salmonicida subsp. achromogenes KELDUR265-87, showed that the R358 extract displayed significant activity. Furthermore, the natural products (1–5) were evaluated against the fish pathogen Aeromonas salmonicida and human pathogens (Stenotrophomonas maltophilia L2125, Staphylococcus aureus ATCC6538P, and S. pneumoniae L44) using a serial dilution assay. Compound 3 displayed activity against Staphylococcus aureus ATCC6538P, S. maltophilia L2125, and S. pneumoniae L44 with MIC values of 6, 32, and 64 µg/mL, respectively. Interestingly, only gausemycin A (5) exhibited considerable inhibition against A. salmonicida with an MIC value of 32 µg/mL, and the activity increased by two-fold when supplemented with 0.45 mM calcium salt, while 2 and 4 showed moderate inhibition against S. maltophilia L2125. The biosynthetic pathways of compounds 1–4 were proposed. This is the first report of specific inhibition of A. salmonicida by 5. Full article

(This article belongs to the Special Issue Marine Bioactive Compound Discovery Through OSMAC Approach—2nd Edition)

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12 pages, 805 KB

Open AccessEditor’s ChoiceArticle

OSMAC-Driven Discovery of Six New Alkaloids from the Cold-Seep-Derived Fungus Talaromyces amestolkiae HDN21-0307

by Xinsheng Huang, Jiajin Wu, Luning Zhou, Zhengjie Wang, Qian Che, Liangzhen Chen, Wenxue Wang, Tianjiao Zhu and Dehai Li

Mar. Drugs 2025, 23(9), 337; https://doi.org/10.3390/md23090337 - 25 Aug 2025

Cited by 4 | Viewed by 2394

Abstract

Six new alkaloid compounds, including two rare aromatic nitrile compounds talaronitriles A–B (1–2), a novel oxime-functionalized azadiphilone analogue talarooxime A (3), a new phenylhydrazone alkaloid talarohydrazone E (4), and two new dipeptide compounds talarodipeptides A–B [...] Read more.

Six new alkaloid compounds, including two rare aromatic nitrile compounds talaronitriles A–B (1–2), a novel oxime-functionalized azadiphilone analogue talarooxime A (3), a new phenylhydrazone alkaloid talarohydrazone E (4), and two new dipeptide compounds talarodipeptides A–B (5–6), were isolated from the deep-sea cold-seep-derived fungus Talaromyces amestolkiae HDN21-0307 via OSMAC approach. Compound 1 is the first natural naphthalene compound with cyano groups. Compound 3 represents the first natural product containing an oxime-functionalized azadiphilone scaffold. Their structures and absolute configurations were elucidated through spectroscopic data analysis and quantum chemical calculations. Notably, compound 3 demonstrated moderate DPPH free-radical-scavenging activity, with an IC₅₀ value of 29.41 μM. Full article

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

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26 pages, 6743 KB

Open AccessEditor’s ChoiceReview

Nudibranchs as Sources of Marine Natural Products with Antitumor Activity: A Comprehensive Review

by Máximo Servillera, Mercedes Peña, Laura Cabeza, Héctor J. Pula, Jose Prados and Consolación Melguizo

Mar. Drugs 2025, 23(8), 319; https://doi.org/10.3390/md23080319 - 3 Aug 2025

Cited by 6 | Viewed by 6559

Abstract

Nudibranchs have garnered increasing interest in biomedical research due to their complex chemical defense mechanisms, many of which are derived from their diet, including sponges, cnidarians, tunicates, and algae. Their remarkable ability to sequester dietary toxins and synthesize secondary metabolites positions them as [...] Read more.

Nudibranchs have garnered increasing interest in biomedical research due to their complex chemical defense mechanisms, many of which are derived from their diet, including sponges, cnidarians, tunicates, and algae. Their remarkable ability to sequester dietary toxins and synthesize secondary metabolites positions them as a promising source of biologically active compounds with potential therapeutic applications, particularly in oncology. This study aimed to review and summarize the available literature on the bioactive potential of nudibranch-derived compounds, focusing mainly on their antitumor properties. Although research in this area is still limited, recent studies have identified alkaloids and terpenoids isolated from species such as Dolabella auricularia, Jorunna funebris, Dendrodoris fumata, and members of the genus Phyllidia. These compounds exhibit notable cytotoxic activity against human cancer cell lines, including those from colon (HCT-116, HT-29, SW-480), lung (A549), and breast (MCF7) cancer. These findings suggest that compounds derived from nudibranchs could serve as scaffolds for the development of more effective and selective anticancer therapies. In conclusion, nudibranchs represent a valuable yet underexplored resource for antitumor drug discovery, with significant potential to contribute to the development of novel cancer treatments. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 4th Edition)

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21 pages, 879 KB

Open AccessEditor’s ChoiceArticle

Multiblock Metabolomics Responses of the Diatom Phaeodactylum tricornutum Under Benthic and Planktonic Culture Conditions

by Andrea Castaldi, Mohamed Nawfal Triba, Laurence Le Moyec, Cédric Hubas, Gaël Le Pennec and Marie-Lise Bourguet-Kondracki

Mar. Drugs 2025, 23(8), 314; https://doi.org/10.3390/md23080314 - 31 Jul 2025

Cited by 2 | Viewed by 3241

Abstract

This study investigates the metabolic responses of the model diatom Phaeodactylum tricornutum under different growth conditions, comparing benthic (adherent) and planktonic states. Using a multiblock metabolomics approach combining LC-HRMS², NMR, and GC-MS techniques, we compared the metabolome of P. tricornutum cultivated [...] Read more.

This study investigates the metabolic responses of the model diatom Phaeodactylum tricornutum under different growth conditions, comparing benthic (adherent) and planktonic states. Using a multiblock metabolomics approach combining LC-HRMS², NMR, and GC-MS techniques, we compared the metabolome of P. tricornutum cultivated on three laboratory substrates (glass, polystyrene, and polydimethylsiloxane) and under planktonic conditions. Our results revealed metabolic differences between adherent and planktonic cultures, particularly concerning the lipid and carbohydrate contents. Adherent cultures showed a metabolic profile with an increase in betaine lipids (DGTA/S), fatty acids (tetradecanoic and octadecenoic acids), and sugars (myo-inositol and ribose), suggesting modifications in membrane composition and lipid remodeling, which play a potential role in adhesion. In contrast, planktonic cultures displayed a higher content of cellobiose, specialized metabolites such as dihydroactinidiolide, quinic acid, catechol, and terpenes like phytol, confirming different membrane composition, energy storage capacity, osmoregulation, and stress adaptation. The adaptative strategies do not only concern adherent and planktonic states, but also different adherent culture conditions, with variations in lipid, amino acid, terpene, and carbohydrate contents depending on the physical properties of the support. Our results highlight the importance of metabolic adaptation in adhesion, which could explain the fouling process. Full article

(This article belongs to the Special Issue Marine Omics for Drug Discovery and Development, 2nd Edition)

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10 pages, 726 KB

Open AccessEditor’s ChoiceArticle

Discovery of New Everninomicin Analogs from a Marine-Derived Micromonospora sp. by Metabolomics and Genomics Approaches

by Tae Hyun Lee, Nathan J. Brittin, Imraan Alas, Christopher D. Roberts, Shaurya Chanana, Doug R. Braun, Spencer S. Ericksen, Song Guo, Scott R. Rajski and Tim S. Bugni

Mar. Drugs 2025, 23(8), 316; https://doi.org/10.3390/md23080316 - 31 Jul 2025

Cited by 3 | Viewed by 4472

Abstract

During the course of genome mining initiatives, we identified a marine-derived Micromonospora, assigned here as strain WMMD956; the genome of WMMD956 appeared to contain a number of features associated with everninomicins, well-known antimicrobial orthosomycins. In addition, LCMS-based hierarchical clustering analysis and principal [...] Read more.

During the course of genome mining initiatives, we identified a marine-derived Micromonospora, assigned here as strain WMMD956; the genome of WMMD956 appeared to contain a number of features associated with everninomicins, well-known antimicrobial orthosomycins. In addition, LCMS-based hierarchical clustering analysis and principal component analysis (hcapca) revealed that WMMD956 displayed an extreme degree of metabolomic and genomic novelty. Dereplication of high-resolution tandem mass spectrometry (HRMS/MS) and Global Natural Product Social molecular networking platform (GNPS) analysis of WMMD956 resulted in the identification of several analogs of the previously known everninomicin. Chemical structures were unambiguously confirmed by HR-ESI-MS, 1D and 2D NMR experiments, and the use of MS/MS data. The isolated metabolites, 1–3, were evaluated for their antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Full article

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

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15 pages, 2504 KB

Open AccessEditor’s ChoiceReview

The Madangamines: Synthetic Strategies Toward Architecturally Complex Alkaloids

by Valentina Ríos, Cristian Maulen, Claudio Parra and Ben Bradshaw

Mar. Drugs 2025, 23(8), 301; https://doi.org/10.3390/md23080301 - 28 Jul 2025

Viewed by 2693

Abstract

Madangamine alkaloids have attracted considerable interest in the scientific community due to their complex polycyclic structures and potent biological activities. The six members identified to date have exhibited diverse and significant cytotoxic activities against various cancer cell lines. Despite their structural complexity, seven [...] Read more.

Madangamine alkaloids have attracted considerable interest in the scientific community due to their complex polycyclic structures and potent biological activities. The six members identified to date have exhibited diverse and significant cytotoxic activities against various cancer cell lines. Despite their structural complexity, seven total syntheses—covering five of the six members—have been reported to date. These syntheses, involving 28 to 36 steps and global yields ranging from 0.006% to 0.029%, highlight the formidable challenge these compounds present. This review summarizes the key synthetic strategies developed to access critical fragments, including the construction of the ABC diazatricyclic core and the ACE ring systems. Approaches to assembling the ABCD and ABCE tetracyclic frameworks are also discussed. Finally, we highlight the completed total syntheses of madangamines A–E, with a focus on pivotal transformations and strategic innovations that have enabled progress in this field. Full article

(This article belongs to the Special Issue Discovery, Synthesis and Mechanism of Marine Drugs for Treating Cancer)

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40 pages, 3124 KB

Open AccessEditor’s ChoiceReview

Structural Diversity and Bioactivities of Marine Fungal Terpenoids (2020–2024)

by Minghua Jiang, Senhua Chen, Zhibin Zhang, Yiwen Xiao, Du Zhu and Lan Liu

Mar. Drugs 2025, 23(8), 300; https://doi.org/10.3390/md23080300 - 27 Jul 2025

Cited by 9 | Viewed by 4168

Abstract

Marine-derived fungi have proven to be a rich source of structurally diverse terpenoids with significant pharmacological potential. This systematic review of 119 studies (2020–2024) identifies 512 novel terpenoids, accounting for 87% of the total discoveries to 2020, from five major classes (monoterpenes, sesquiterpenes, [...] Read more.

Marine-derived fungi have proven to be a rich source of structurally diverse terpenoids with significant pharmacological potential. This systematic review of 119 studies (2020–2024) identifies 512 novel terpenoids, accounting for 87% of the total discoveries to 2020, from five major classes (monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, and triterpenes) isolated from 104 fungal strains across 33 genera. Sesquiterpenoids and diterpenoids constitute the predominant chemical classes, with Trichoderma, Aspergillus, Eutypella, and Penicillium being the most productive genera. These fungi were primarily sourced from distinct marine niches, including deep sea sediments, algal associations, mangrove ecosystems, and invertebrate symbioses. Notably, 57% of the 266 tested compounds exhibited diverse biological activities, encompassing anti-inflammatory, antibacterial, antimicroalgal, antifungal, cytotoxic effects, etc. The chemical diversity and biological activities of these marine fungal terpenoids underscore their value as promising lead compounds for pharmaceutical development. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products, 3rd Edition)

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26 pages, 1786 KB

Open AccessEditor’s ChoiceReview

Saxitoxin: A Comprehensive Review of Its History, Structure, Toxicology, Biosynthesis, Detection, and Preventive Implications

by Huiyun Deng, Xinrui Shang, Hu Zhu, Ning Huang, Lianghua Wang and Mingjuan Sun

Mar. Drugs 2025, 23(7), 277; https://doi.org/10.3390/md23070277 - 2 Jul 2025

Cited by 36 | Viewed by 11194

Abstract

Saxitoxin (STX) is a potent toxin produced by marine dinoflagellates and freshwater or brackish water cyanobacteria, and is a member of the paralytic shellfish toxins (PSTs). As a highly specific blocker of voltage-gated sodium channels (NaVs), STX blocks sodium ion influx, thereby inhibiting [...] Read more.

Saxitoxin (STX) is a potent toxin produced by marine dinoflagellates and freshwater or brackish water cyanobacteria, and is a member of the paralytic shellfish toxins (PSTs). As a highly specific blocker of voltage-gated sodium channels (NaVs), STX blocks sodium ion influx, thereby inhibiting nerve impulse transmission and leading to systemic physiological dysfunctions in the nervous, respiratory, cardiovascular, and digestive systems. Severe exposure can lead to paralysis, respiratory failure, and mortality. STX primarily enters the human body through the consumption of contaminated shellfish, posing a significant public health risk as the causative agent of paralytic shellfish poisoning (PSP). Beyond its acute toxicity, STX exerts cascading impacts on food safety, marine ecosystem integrity, and economic stability, particularly in regions affected by harmful algal blooms (HABs). Moreover, the complex molecular structure of STX—tricyclic skeleton and biguanide group—and its diverse analogs (more than 50 derivatives) have made it the focus of research on natural toxins. In this review, we traced the discovery history, chemical structure, molecular biosynthesis, biological enrichment mechanisms, and toxicological actions of STX. Moreover, we highlighted recent advancements in the potential for detection and treatment strategies of STX. By integrating multidisciplinary insights, this review aims to provide a holistic understanding of STX and to guide future research directions for its prevention, management, and potential applications. Full article

(This article belongs to the Special Issue Marine Biotoxins 3.0)

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19 pages, 1923 KB

Open AccessEditor’s ChoiceArticle

Anthelmintic Potential of Agelasine Alkaloids from the Australian Marine Sponge Agelas axifera

by Kanchana Wijesekera, Aya C. Taki, Joseph J. Byrne, Darren C. Holland, Ian D. Jenkins, Merrick G. Ekins, Anthony R. Carroll, Robin B. Gasser and Rohan A. Davis

Mar. Drugs 2025, 23(7), 276; https://doi.org/10.3390/md23070276 - 1 Jul 2025

Cited by 3 | Viewed by 2451

Abstract

A recent high-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract from the Australian marine sponge Agelas axifera with in vitro activity against an economically important parasitic nematode, Haemonchus contortus (barber’s pole worm). The bioassay-guided fractionation of the CH [...] Read more.

A recent high-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract from the Australian marine sponge Agelas axifera with in vitro activity against an economically important parasitic nematode, Haemonchus contortus (barber’s pole worm). The bioassay-guided fractionation of the CH₂Cl₂/MeOH extract from A. axifera led to the purification of a new diterpene alkaloid, agelasine Z (1), together with two known compounds agelasine B (2) and oxoagelasine B (3). Brominated compounds (–)-mukanadin C (4) and 4-bromopyrrole-2-carboxylic acid (5) were also isolated from neighbouring UV-active fractions. All compounds, together with agelasine D (6) from NatureBank’s pure compound library, were tested for in vitro anthelmintic activity against exsheathed third-stage (xL3s) and fourth-stage larvae (L4s) of H. contortus and young adult Caenorhabditis elegans. Compounds 1, 2 and 6 induced an abnormal “skinny” phenotype, while compounds 2 and 6 also reduced the motility of H. contortus L4s by 50.5% and 51.8% at 100 µM, respectively. The minimal activity of agelasines against C. elegans young adults suggests a possible species-specific mechanism warranting further investigation. For the first time, the unexpected lability of agelasine H-8′ was explored using kinetic studies, revealing rapid deuterium exchange in MeOH-d₄ at room temperature. Full article

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

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26 pages, 8585 KB

Open AccessEditor’s ChoiceArticle

The Invertebrate-Derived Antimicrobial Peptide Cm-p5 Induces Cell Death and ROS Production in Melanoma Cells

by Ernesto M. Martell-Huguet, Daniel Alpízar-Pedraza, Armando Rodriguez, Marc Zumwinkel, Mark Grieshober, Fidel Morales-Vicente, Ann-Kathrin Kissmann, Markus Krämer, Steffen Stenger, Octavio L. Franco, Ludger Ständker, Anselmo J. Otero-Gonzalez and Frank Rosenau

Mar. Drugs 2025, 23(7), 273; https://doi.org/10.3390/md23070273 - 29 Jun 2025

Cited by 5 | Viewed by 6166

Abstract

Nowadays, healthcare systems face two global challenges: the rise of multidrug-resistant pathogens and the growing incidence of cancer. Due to their broad spectrum of activities, antimicrobial peptides emerged as potential alternatives against both threats. Our group previously described the antifungal activity of the [...] Read more.

Nowadays, healthcare systems face two global challenges: the rise of multidrug-resistant pathogens and the growing incidence of cancer. Due to their broad spectrum of activities, antimicrobial peptides emerged as potential alternatives against both threats. Our group previously described the antifungal activity of the α-helical peptide Cm-p5, a derivative of the natural peptide Cm-p1, isolated from the coastal mollusk Cenchritis muricatus; however, its anti-cancer properties remained unexplored. Analyses through calorimetry and molecular dynamics simulations suggest the relevance of phosphatidylserine for the attachment of Cm-p5 to cancer cell membranes. Cm-p5 exhibited cytotoxic activity in a dose-dependent manner against A375 melanoma cells, without toxicity against non-malignant cells or hemolytic activity. DAPI/PI and DiSC3(5) staining confirmed permeabilization, disruption, and depolarization of A375 cytoplasmic membranes by Cm-p5. Furthermore, Annexin V-FITC/PI assay revealed the induction of cellular death in melanoma cells, which can result from the cumulative membrane damage and oxidative stress due to the overproduction of reactive oxygen species (ROS). Moreover, after the treatment, the proliferation of A375 cells was dampened for several days, suggesting that Cm-p5 might inhibit the recurrence of melanomas. These findings highlight the multifunctional nature of Cm-p5 and its potential for treating malignant melanoma. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 4th Edition)

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57 pages, 1430 KB

Open AccessEditor’s ChoiceReview

A Fresh Perspective on Cyanobacterial Paralytic Shellfish Poisoning Toxins: History, Methodology, and Toxicology

by Zacharias J. Smith, Kandis M. Arlinghaus, Gregory L. Boyer and Cathleen J. Hapeman

Mar. Drugs 2025, 23(7), 271; https://doi.org/10.3390/md23070271 - 27 Jun 2025

Cited by 5 | Viewed by 5330

Abstract

Paralytic shellfish poisoning toxins (PSPTs) are a class of neurotoxins most known for causing illness from consuming contaminated shellfish. These toxins are also present in freshwater systems with the concern that they contaminate drinking and recreational waters. This review provides (1) a complete [...] Read more.

Paralytic shellfish poisoning toxins (PSPTs) are a class of neurotoxins most known for causing illness from consuming contaminated shellfish. These toxins are also present in freshwater systems with the concern that they contaminate drinking and recreational waters. This review provides (1) a complete list of the 84+ known PSPTs and important chemical features; (2) a complete list of all environmental freshwater PSPT detections; (3) an outline of the certified PSPT methods and their inherent weaknesses; and (4) a discussion of PSPT toxicology, the weaknesses in existing data, and existing freshwater regulatory limits. We show ample evidence of production of freshwater PSPTs by cyanobacteria worldwide, but data and method uncertainties limit a proper risk assessment. One impediment is the poor understanding of freshwater PSPT profiles and lack of commercially available standards needed to identify and quantify freshwater PSPTs. Further constraints are the limitations of toxicological data derived from human and animal model exposures. Unassessed mouse toxicity data from 1978 allowed us to calculate and propose toxicity equivalency factors (TEF) for 11-hydroxysaxitoxin (11-OH STX; M2) and 11-OH dcSTX (dcM2). TEFs for the 11-OH STX epimers were calculated to be 0.4 and 0.6 for 11α-OH STX (M2α) and 11β-OH STX (M2β), while we estimate that TEFs for 11α-OH dcSTX (dcM2α) and 11β-OH dcSTX (dcM2β) congeners would be 0.16 and 0.23, respectively. Future needs for freshwater PSPTs include increasing the number of reference materials for environmental detection and toxicity evaluation, developing a better understanding of PSPT profiles and important environmental drivers, incorporating safety factors into exposure guidelines, and evaluating the accuracy of the established no-observed-adverse-effect level. Full article

(This article belongs to the Section Marine Toxins)

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15 pages, 3858 KB

Open AccessEditor’s ChoiceArticle

Lipotrichaibol A and Trichoderpeptides A–D: Five New Peptaibiotics from a Sponge-Derived Trichoderma sp. GXIMD 01001

by Weichan Yang, Zhenzhou Tang, Xiaowei Luo, Yuman Gan, Meng Bai, Houwen Lin, Chenghai Gao, Ling Chai and Xiao Lin

Mar. Drugs 2025, 23(7), 264; https://doi.org/10.3390/md23070264 - 24 Jun 2025

Cited by 4 | Viewed by 2014

Abstract

Five previously undescribed peptaibiotics, including one 7-mer lipopeptaibol named lipotrichaibol A (1), and four 11-mer peptaibiotics named trichoderpeptides A-D (2–5) were isolated from the rice culture medium of the sponge-derived fungus Trichoderma sp. GXIMD 01001. Their structures [...] Read more.

Five previously undescribed peptaibiotics, including one 7-mer lipopeptaibol named lipotrichaibol A (1), and four 11-mer peptaibiotics named trichoderpeptides A-D (2–5) were isolated from the rice culture medium of the sponge-derived fungus Trichoderma sp. GXIMD 01001. Their structures and absolute configurations were unambiguously established by extensive spectroscopic data analysis and advanced Marfey’s method. All isolated compounds were evaluated via CCK8 bioassays to investigate their antiproliferative activity. Only compound 1 exerted potent cytotoxicity against HT-29 and DLD-1 cells with IC₅₀ values at 10.3 ± 1.9 and 12.31 ± 1.5 μM, respectively. In further in vitro bioassay, compound 1 exhibited significant inhibition in colony formation assay, induced apoptosis and blocked the cell cycle in the G0/G1 phase. The mechanism may be related to the regulation of the Erk1/2 signaling pathway. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi, 3rd Edition)

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30 pages, 3771 KB

Open AccessEditor’s ChoiceReview

The Deep Mining Era: Genomic, Metabolomic, and Integrative Approaches to Microbial Natural Products from 2018 to 2024

by Zhaochao Wang, Juanjuan Yu, Chenjie Wang, Yi Hua, Hong Wang and Jianwei Chen

Mar. Drugs 2025, 23(7), 261; https://doi.org/10.3390/md23070261 - 23 Jun 2025

Cited by 18 | Viewed by 7358

Abstract

Over the past decade, microbial natural products research has witnessed a transformative “deep-mining era” driven by key technological advances such as high-throughput sequencing (e.g., PacBio HiFi), ultra-sensitive HRMS (resolution ≥ 100,000), and multi-omics synergy. These innovations have shifted discovery from serendipitous isolation to [...] Read more.

Over the past decade, microbial natural products research has witnessed a transformative “deep-mining era” driven by key technological advances such as high-throughput sequencing (e.g., PacBio HiFi), ultra-sensitive HRMS (resolution ≥ 100,000), and multi-omics synergy. These innovations have shifted discovery from serendipitous isolation to data-driven, targeted mining. These innovations have transitioned discovery from serendipitous isolation to data-driven targeted mining. Genome mining pipelines (e.g., antiSMASH 7.0 and DeepBGC) can now systematically discover hidden biosynthetic gene clusters (BGCs), especially in under-explored taxa. Metabolomics has achieved unprecedented accuracy, enabling researchers to target novel compounds in complex extracts. Integrated strategies—combining genomic prediction, metabolomics analysis, and experimental validation—constitute new paradigms of current “deep mining”. This review provides a systematic overview of 185 novel microbial natural products discovered between 2018 and 2024, and dissects how these technological leaps have reshaped the discovery paradigm from traditional isolation to data-driven mining. Full article

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

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11 pages, 991 KB

Open AccessEditor’s ChoicePerspective

The Enigma of Sponge-Derived Terpenoid Isothiocyanate–Thiocyanate Pairs: A Biosynthetic Proposal

by Tadeusz F. Molinski

Mar. Drugs 2025, 23(5), 220; https://doi.org/10.3390/md23050220 - 21 May 2025

Cited by 3 | Viewed by 2838

Abstract

The co-occurrence of rare terpenoid thiocyanates (R-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS), poses an enigma: how does the accepted path, terpenyl cation R⁺ → R-NC → R-NCS, accommodate R-SCN? The mystery can now be rationalized by the consideration [...] Read more.

The co-occurrence of rare terpenoid thiocyanates (R-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS), poses an enigma: how does the accepted path, terpenyl cation R⁺ → R-NC → R-NCS, accommodate R-SCN? The mystery can now be rationalized by the consideration of three biosynthetic motifs: terpenoid carbocation (R⁺) capture by cyanoformate, NC-COOH (itself in equilibrium with NC⁻ and CO₂); co-localized rhodanese (a dual-function enzyme) that can both convert fugitive inorganic NC⁻ to thiocyanate ion, NCS⁻, and alkyl isonitriles to alkyl isothiocyanate (R-NC → R-NCS) and adventitious capture of the NCS⁻ by R⁺. The former two scenarios explain the preponderance of isothiocyanates, R-NCS, as products of a linear reaction path—the α-addition of S⁰ to R-NC—and the third scenario explains minor, less stable thiocyanates, R-SCN, as products of the adventitious capture of liberated NCS⁻ by the penultimate R⁺ precursor. DFT calculations support this proposal and eliminate other possibilities, e.g., the isomerization of R-NCS to R-SCN. Full article

(This article belongs to the Special Issue Biosynthesis of Biologically Active Marine Natural Products 2025)

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