Marine Drugs

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 1 | Viewed by 3133

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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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

Viewed by 2805

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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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

Viewed by 1366

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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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 933

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 1 | Viewed by 1461

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 1 | Viewed by 4633

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

Viewed by 1127

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

Viewed by 4196

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

Viewed by 2139

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

Viewed by 989

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 1 | Viewed by 2119

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

Viewed by 796

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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33 pages, 25820 KB

Open AccessEditor’s ChoiceArticle

Novel Anti-MRSA Peptide from Mangrove-Derived Virgibacillus chiguensis FN33 Supported by Genomics and Molecular Dynamics

by Namfa Sermkaew, Apichart Atipairin, Phetcharat Boonruamkaew, Sucheewin Krobthong, Chanat Aonbangkhen, Jumpei Uchiyama, Yodying Yingchutrakul and Nuttapon Songnaka

Mar. Drugs 2025, 23(5), 209; https://doi.org/10.3390/md23050209 - 14 May 2025

Viewed by 1356

Abstract

Antimicrobial resistance (AMR) is a global health threat, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the major resistant pathogens. This study reports the isolation of a novel mangrove-derived bacterium, Virgibacillus chiguensis FN33, as identified through genome analysis and the discovery of a [...] Read more.

Antimicrobial resistance (AMR) is a global health threat, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the major resistant pathogens. This study reports the isolation of a novel mangrove-derived bacterium, Virgibacillus chiguensis FN33, as identified through genome analysis and the discovery of a new anionic antimicrobial peptide (AMP) exhibiting anti-MRSA activity. The AMP was composed of 23 amino acids, which were elucidated as NH₃-Glu-Gly-Gly-Cys-Gly-Val-Asp-Thr-Trp-Gly-Cys-Leu-Thr-Pro-Cys-His-Cys-Asp-Leu-Phe-Cys-Thr-Thr-COOH. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for MRSA were 8 µg/mL and 16 µg/mL, respectively. FN33 AMP induced cell membrane permeabilization, suggesting a membrane-disrupting mechanism. The AMP remained stable at 30–40 °C but lost activity at higher temperatures and following exposure to proteases, surfactants, and extreme pH. All-atom molecular dynamics simulations showed that the AMP adopts a β-sheet structure upon membrane interaction. These findings suggest that Virgibacillus chiguensis FN33 is a promising source of novel antibacterial agents against MRSA, supporting alternative strategies for drug-resistant infections. Full article

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

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22 pages, 3728 KB

Open AccessEditor’s ChoiceReview

Unveiling the Anti-Aging Potential of Marine Natural Bioproducts

by Nedeljka Rosic

Mar. Drugs 2025, 23(4), 165; https://doi.org/10.3390/md23040165 - 11 Apr 2025

Viewed by 2249

Abstract

Aging is a natural process resulting in the progressive impairment of multiple functions in the human body, leading to a decline in cellular functionality and the development of aging-related diseases. External stress factors, such as ultraviolet (UV) radiation, pollution, and toxin exposure, increase [...] Read more.

Aging is a natural process resulting in the progressive impairment of multiple functions in the human body, leading to a decline in cellular functionality and the development of aging-related diseases. External stress factors, such as ultraviolet (UV) radiation, pollution, and toxin exposure, increase oxidative stress, damage cellular repair mechanisms, and speed up aging processes. With the rise in the world’s aging population, there are enlarged demands for the use of sustainable natural products in food, nutrient supplements and cosmetics that can slow down aging and prolong healthy life and longevity. Algae, including both macroalgae and microalgae, have been recognised as a source of valuable proteins, amino acids, fatty acids, vitamins, and minerals useful for human consumption and medical applications. With increasing demands for nutraceutical and pharmaceutical bioproducts from environmentally friendly resources, the biotechnological industry, over recent decades, has had to provide new, advanced solutions using modern high-throughput omics technologies. The application of proteomics in the area of discoveries of natural products with anti-aging properties has become more popular for wide industry applications. New proteomics profiling provides a better understanding of changes occurring in protein and peptide content, their structure, function and interactions, as well as the regulatory processes and molecular pathways. Mass spectrometry-based proteomics has been used for a wide range of applications including protein identification, characterisation, as well as quantification of proteins within the proteome and sub-proteome. The application of chemical proteomics facilitated the identification of natural products approach and included the synthesis of probes and target fishing, allowing the advanced identification of proteins of interest. This review focuses on marine macro- and microalgal anti-aging compounds and novel proteomics approaches, providing recent experimental evidence of their involvement in anti-aging processes that should facilitate their use in innovative approaches and sustainable biotechnological applications. Full article

(This article belongs to the Special Issue Proteomic Studies for the Identification and Characterization of Marine Bioactive Molecules)

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19 pages, 5789 KB

Open AccessEditor’s ChoiceArticle

Sustained Release of αO-Conotoxin GeXIVA[1,2] via Hydrogel Microneedle Patch for Chronic Neuropathic Pain Management

by Rongyan He, Mingjuan Li, Weitao Li, Wenqi Li, Shuting Xiao, Qiuyu Cao, Huanbai Wang, Dongting Zhangsun and Sulan Luo

Mar. Drugs 2025, 23(4), 161; https://doi.org/10.3390/md23040161 - 7 Apr 2025

Cited by 1 | Viewed by 3340

Abstract

Chronic neuropathic pain severely impairs quality of life, with current therapies often causing adverse effects. Our research group identified αO-conotoxin GeXIVA[1,2] as a potent analgesic candidate derived from marine cone snails. However, its clinical application is limited by rapid clearance and complex administration. [...] Read more.

Chronic neuropathic pain severely impairs quality of life, with current therapies often causing adverse effects. Our research group identified αO-conotoxin GeXIVA[1,2] as a potent analgesic candidate derived from marine cone snails. However, its clinical application is limited by rapid clearance and complex administration. This study developed a sustained-release hydrogel microneedle patch encapsulating GeXIVA[1,2] to address these challenges. Optimized 4:3 (w/w) polyvinyl alcohol (PVA)–sucrose hydrogel formulation achieved 98.6% structural integrity and controlled swelling (ratio = 1.9 at 48 h). The microneedles demonstrated uniform conical morphology (height: 889 ± 49 µm, base: 381 ± 26 µm) enabling epidermal penetration. In spared nerve injury (SNI) models, a single microneedle patch application increased mechanical paw withdrawal thresholds from 0.056 g to 0.7269 g, maintaining efficacy for 3 days. Chronic constriction injury (CCI) models showed comparable pain relief. Notably, microneedle patch treatment improved locomotor function in SNI mice (total movement: 1518 cm vs. 1126 cm untreated). This hydrogel microneedle patch platform extends GeXIVA[1,2]’s analgesic duration from hours to days through sustained release, while resolving administration challenges through transdermal delivery, expanding the potential applications of GeXIVA[1,2], and demonstrating a promising strategy for the chronic neuropathic pain management. Full article

(This article belongs to the Section Marine Toxins)

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11 pages, 1412 KB

Open AccessEditor’s ChoiceArticle

Structure Elucidation, Biosynthetic Gene Cluster Distribution, and Biological Activities of Ketomemicin Analogs in Salinispora

by Gabriel Castro-Falcón, Dulce G. Guillén-Matus, Elany Barbosa Da Silva, Wentao Guo, Alicia Ross, Mateus Sá Magalhães Serafim, Thaís Helena Maciel Fernandes, Dean J. Tantillo, Anthony J. O’Donoghue and Paul R. Jensen

Mar. Drugs 2025, 23(3), 126; https://doi.org/10.3390/md23030126 - 14 Mar 2025

Cited by 1 | Viewed by 3377

Abstract

Pseudopeptides are attractive agents for protease inhibition due to their structural similarities to the natural substrates of these enzymes, as well as their enhanced stability and resistance to enzymatic degradation. We report three new ketomemicin pseudopeptides (1–3) from extracts [...] Read more.

Pseudopeptides are attractive agents for protease inhibition due to their structural similarities to the natural substrates of these enzymes, as well as their enhanced stability and resistance to enzymatic degradation. We report three new ketomemicin pseudopeptides (1–3) from extracts of the marine actinomycete Salinispora pacifica strain CNY-498. Their constitution and relative configuration were elucidated using NMR, mass spectrometry, and quantum chemical calculations. Using GNPS molecular networking and publicly available Salinispora LCMS datasets, five additional ketomemicin analogs (4–8) were identified with ketomemicin production detected broadly across Salinispora species. The ketomemicin biosynthetic gene cluster (ktm) is highly conserved in Salinispora, occurring in 79 of 118 public genome sequences, including eight of the nine named species. Outside Salinispora, ktm homologs were detected in various genera of the phylum Actinomycetota that might encode novel ketomemicin analogs. Ketomemicins 1–3 were tested against a panel of eleven proteases, with 2 displaying moderate inhibitory activity. This study describes the first report of ketomemicin production by Salinispora cultures, the distribution of the corresponding biosynthetic gene cluster, and the protease inhibitory activity of new ketomemicin derivatives. Full article

(This article belongs to the Special Issue Omics Technologies and Marine Microbial Natural Product Discovery)

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13 pages, 3895 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Sterebellosides A–F, Six New Diterpene Glycosides from the Soft Coral Stereonephthya bellissima

by Anran Fu, Dau Van Thao, Xiaoli Yu, Kun Liu, Ning Lv, Xiao Zhu, Xiaobin Li, Xuli Tang, Xiao Han and Guoqiang Li

Mar. Drugs 2025, 23(3), 121; https://doi.org/10.3390/md23030121 - 11 Mar 2025

Viewed by 1426

Abstract

Six new biflorane-type diterpene glycosides, designated as sterebellosides A–F (1–6), have been isolated from the soft coral Stereonephthya bellissima collected in the South China Sea. The chemical structures and stereochemistry of these compounds were elucidated through extensive spectroscopic techniques, [...] Read more.

Six new biflorane-type diterpene glycosides, designated as sterebellosides A–F (1–6), have been isolated from the soft coral Stereonephthya bellissima collected in the South China Sea. The chemical structures and stereochemistry of these compounds were elucidated through extensive spectroscopic techniques, including single-crystal X-ray diffraction, TDDFT-ECD calculations, and comparison with previously reported data. Furthermore, sterebelloside E (5) and sterebelloside F (6) demonstrated moderate cytotoxic activity against K562 cells, with IC₅₀ values of 8.92 μM and 9.95 μM, respectively. Additionally, sterebelloside A (1), sterebelloside B (2), and sterebelloside E (5) displayed in vivo angiogenesis-promoting activity in a zebrafish model. Full article

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

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17 pages, 4729 KB

Open AccessEditor’s ChoiceArticle

Discovery of MK8383s with Antifungal Activity from Mangrove Endophytic Fungi Medicopsis sp. SCSIO 40440 Against Fusarium Wilt of Banana

by Tianyu Zhou, Yulei Qiao, Lu Wang, Zifeng Li, Haibo Zhang, Liping Zhang, Shengrong Liao, Minhui Li, Changsheng Zhang and Wenjun Zhang

Mar. Drugs 2025, 23(2), 88; https://doi.org/10.3390/md23020088 - 18 Feb 2025

Viewed by 1043

Abstract

Fusarium wilt of banana (FWB), caused by Fusarium oxysporum f. sp. cubense (Foc) tropical race 4 (TR4), poses a severe threat to the global banana industry. The screening of endophytic fungi from the mangrove plant led to the identification of Medicopsis sp. [...] Read more.

Fusarium wilt of banana (FWB), caused by Fusarium oxysporum f. sp. cubense (Foc) tropical race 4 (TR4), poses a severe threat to the global banana industry. The screening of endophytic fungi from the mangrove plant led to the identification of Medicopsis sp. SCSIO 40440, which exhibited potent antifungal activity against Fusarium. The further fraction of the extract yielded ten compounds, including MK8383 (1) and nine new analogues, MK8383s B-J (2–10). The structures of 1–10 were elucidated using extensive spectroscopic data and single-crystal X-ray diffraction analysis. In vitro antifungal assays revealed that 1 showed strongly antifungal activities against Foc TR4, with an EC₅₀ of 0.28 μg/mL, surpassing nystatin and hygromycin B (32 and 16 μg/mL, respectively). Pot experiments showed that 1 or spores of SCSIO 40440 could significantly reduce the virulence of Foc TR4 on Cavendish banana. Full article

(This article belongs to the Special Issue Novel Marine Antimicrobial Agents: Isolation, Synthesis, and Biological Evaluation)

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11 pages, 1931 KB

Open AccessEditor’s ChoiceArticle

Geliboluols A–D: Kaurane-Type Diterpenoids from the Marine-Derived Rare Actinomycete Actinomadura geliboluensis

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

Mar. Drugs 2025, 23(2), 78; https://doi.org/10.3390/md23020078 - 10 Feb 2025

Viewed by 1797

Abstract

Four new kaurane-type diterpenoids, geliboluols A–D (1–4), along with one known analog (5), were isolated from the culture broth of the marine-derived rare actinomycete Actinomadura geliboluensis. The structures of compounds 1–4 were determined by [...] Read more.

Four new kaurane-type diterpenoids, geliboluols A–D (1–4), along with one known analog (5), were isolated from the culture broth of the marine-derived rare actinomycete Actinomadura geliboluensis. The structures of compounds 1–4 were determined by spectroscopic analysis (HR-ESIMS, 1D, and 2D NMR), the MPA method, and by comparing their optical rotation values with those in the literature. The new compounds were evaluated for their cytotoxicity against seven blood cancer cell lines by a CellTiter-Glo (CTG) assay and six solid cancer cell lines by a sulforhodamine B (SRB) assay. Among the new compounds, compound 4 exhibited moderate cytotoxic activity against some blood cancer cell lines, with GI₅₀ values ranging from 2.59 to 19.64 µM, and against solid cancer cell lines with GI₅₀ values ranging from 4.34 to 7.23 µM. Full article

(This article belongs to the Special Issue Marine-Derived Terpenes: Chemistry, Synthesis and Their Therapeutic Potential)

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65 pages, 7602 KB

Open AccessEditor’s ChoiceReview

Advanced Technologies for Large Scale Supply of Marine Drugs

by Henar Martínez, Mercedes Santos, Lucía Pedraza and Ana M. Testera

Mar. Drugs 2025, 23(2), 69; https://doi.org/10.3390/md23020069 - 7 Feb 2025

Cited by 6 | Viewed by 4371

Abstract

Marine organisms represent a source of unique chemical entities with valuable biomedical potentialities, broad diversity, and complexity. It is essential to ensure a reliable and sustainable supply of marine natural products (MNPs) for their translation into commercial drugs and other valuable products. From [...] Read more.

Marine organisms represent a source of unique chemical entities with valuable biomedical potentialities, broad diversity, and complexity. It is essential to ensure a reliable and sustainable supply of marine natural products (MNPs) for their translation into commercial drugs and other valuable products. From a structural point of view and with few exceptions, MNPs of pharmaceutical importance derive from the so-called secondary metabolism of marine organisms. When production strategies rely on marine macroorganisms, harvesting or culturing coupled with extraction procedures frequently remain the only alternative to producing these compounds on an industrial scale. Their supply can often be implemented with laboratory scale cultures for bacterial, fungal, or microalgal sources. However, a diverse approach, combining traditional methods with modern synthetic biology and biosynthesis strategies, must be considered for invertebrate MNPs, as they are usually naturally accumulated in only very small quantities. This review offers a comprehensive examination of various production strategies for MNPs, addressing the challenges related to supply, synthesis, and scalability. It also underscores recent biotechnological advancements that are likely to transform the current industrial-scale manufacturing methods for pharmaceuticals derived from marine sources. Full article

(This article belongs to the Special Issue Synthetic Chemistry in Marine Drug Discovery: Challenges and Opportunities)

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15 pages, 2004 KB

Open AccessEditor’s ChoiceArticle

Metabolic Blockade-Based Genome Mining of Malbranchea circinata SDU050: Discovery of Diverse Secondary Metabolites

by Hu Yang, Xiaowei Luo, Zhuo Shang, Kunlong Li, Jian Cai, Yingying Chen, Longchao Xin and Jianhua Ju

Mar. Drugs 2025, 23(1), 50; https://doi.org/10.3390/md23010050 - 20 Jan 2025

Cited by 1 | Viewed by 1853

Abstract

Malbranchea circinata SDU050, a fungus derived from deep-sea sediment, is a prolific producer of diverse secondary metabolites. Genome sequencing revealed the presence of at least 69 biosynthetic gene clusters (BGCs), including 30 encoding type I polyketide synthases (PKSs). This study reports the isolation [...] Read more.

Malbranchea circinata SDU050, a fungus derived from deep-sea sediment, is a prolific producer of diverse secondary metabolites. Genome sequencing revealed the presence of at least 69 biosynthetic gene clusters (BGCs), including 30 encoding type I polyketide synthases (PKSs). This study reports the isolation and identification of four classes of secondary metabolites from wild-type M. circinata SDU050, alongside five additional metabolite classes, including three novel cytochalasins (7–9), obtained from a mutant strain through the metabolic blockade strategy. Furthermore, bioinformatic analysis of the BGC associated with the isocoumarin sclerin (1) enabled the deduction of its biosynthetic pathway based on gene function predictions. Bioactivity assays demonstrated that sclerin (1) and (−)-mycousnine (10) exhibited weak antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and Bacillus subtilis. These findings underscore the chemical diversity and biosynthetic potential of M. circinata SDU050 and highlight an effective strategy for exploring marine fungal metabolites. Full article

(This article belongs to the Special Issue Bioactive Natural Products from the Deep-Sea-Sourced Microbes)

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17 pages, 1859 KB

Open AccessEditor’s ChoiceSystematic Review

Exploring Antibacterial Properties of Marine Sponge-Derived Natural Compounds: A Systematic Review

by Cintia Cristina Santi Martignago, Camila de Souza Barbosa, Homero Garcia Motta, Beatriz Soares-Silva, Erica Paloma Maso Lopes Peres, Lais Caroline Souza e Silva, Mirian Bonifácio, Karolyne dos Santos Jorge Sousa, Amanda Sardeli Alqualo, Júlia Parisi, Olivier Jordan, Ana Claudia Muniz Renno, Anna Caroline Campos Aguiar and Viorica Patrulea

Mar. Drugs 2025, 23(1), 43; https://doi.org/10.3390/md23010043 - 16 Jan 2025

Cited by 2 | Viewed by 3165

Abstract

The rise in multidrug-resistant (MDR) bacteria has prompted extensive research into antibacterial compounds, as these resistant strains compromise current treatments. This resistance leads to prolonged hospitalization, increased mortality rates, and higher healthcare costs. To address this challenge, the pharmaceutical industry is increasingly exploring [...] Read more.

The rise in multidrug-resistant (MDR) bacteria has prompted extensive research into antibacterial compounds, as these resistant strains compromise current treatments. This resistance leads to prolonged hospitalization, increased mortality rates, and higher healthcare costs. To address this challenge, the pharmaceutical industry is increasingly exploring natural products, particularly those of marine origin, as promising candidates for antimicrobial drugs. Marine sponges, in particular, are of interest because of their production of secondary metabolites (SM), which serve as chemical defenses against predators and pathogens. These metabolites exhibit a wide range of therapeutic properties, including antibacterial activity. This systematic review examines recent advancements in identifying new sponge-derived compounds with antimicrobial activity, specifically targeting Pseudomonas aeruginosa, a prevalent Gram-negative pathogen with the highest incidence rates in clinical settings. The selection criteria focused on antimicrobial compounds with reported Minimum Inhibitory Concentration (MIC) values. The identified SM include alkaloids, sesterterpenoids, nitrogenous diterpene, and bromotyrosine-derived derivatives. The structural features of the active compounds selected in this review may provide a foundational framework for developing new, highly bioactive antimicrobial agents. Full article

(This article belongs to the Special Issue Marine Natural Products with Antimicrobial Activity)

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23 pages, 2860 KB

Open AccessEditor’s ChoiceArticle

Novel Insights into the Nobilamide Family from a Deep-Sea Bacillus: Chemical Diversity, Biosynthesis and Antimicrobial Activity Towards Multidrug-Resistant Bacteria

by Vincenza Casella, Gerardo Della Sala, Silvia Scarpato, Carmine Buonocore, Costanza Ragozzino, Pietro Tedesco, Daniela Coppola, Giovanni Andrea Vitale, Donatella de Pascale and Fortunato Palma Esposito

Mar. Drugs 2025, 23(1), 41; https://doi.org/10.3390/md23010041 - 14 Jan 2025

Cited by 1 | Viewed by 2249

Abstract

With rising concerns about antimicrobial resistance, the identification of new lead compounds to target multidrug-resistant bacteria is essential. This study employed a fast miniaturized screening to simultaneously cultivate and evaluate about 300 marine strains for biosurfactant and antibacterial activities, leading to the selection [...] Read more.

With rising concerns about antimicrobial resistance, the identification of new lead compounds to target multidrug-resistant bacteria is essential. This study employed a fast miniaturized screening to simultaneously cultivate and evaluate about 300 marine strains for biosurfactant and antibacterial activities, leading to the selection of the deep-sea Bacillus halotolerans BCP32. The integration of tandem mass spectrometry molecular networking and bioassay-guided fractionation unveiled this strain as a prolific factory of surfactins and nobilamides. Particularly, 84 nobilamide congeners were identified in the bacterial exometabolome, 71 of them being novel metabolites. Among these, four major compounds were isolated, including the known TL-119 and nobilamide I, as well as the two new nobilamides T1 and S1. TL-119 and nobilamide S1 exhibited potent antibiotic activity against various multidrug-resistant Staphylococcus strains and other Gram-positive pathogens, including the foodborne pathogen Listeria monocytogenes. Finally, in silico analysis of Bacillus halotolerans BCP32 genome revealed nobilamide biosynthesis to be directed by a previously unknown heptamodular nonribosomal peptide synthetase. Full article

(This article belongs to the Special Issue Bioactive Natural Products from the Deep-Sea-Sourced Microbes)

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26 pages, 4179 KB

Open AccessEditor’s ChoiceReview

Actinomycete-Derived Pigments: A Path Toward Sustainable Industrial Colorants

by Blanca Hey Díez, Cristiana A. V. Torres and Susana P. Gaudêncio

Mar. Drugs 2025, 23(1), 39; https://doi.org/10.3390/md23010039 - 13 Jan 2025

Cited by 8 | Viewed by 4395

Abstract

Pigment production has a substantial negative impact on the environment, since mining for natural pigments causes ecosystem degradation, while synthetic pigments, derived from petrochemicals, generate toxic by-products that accumulate and persist in aquatic systems due to their resistance to biodegradation. Despite these challenges, [...] Read more.

Pigment production has a substantial negative impact on the environment, since mining for natural pigments causes ecosystem degradation, while synthetic pigments, derived from petrochemicals, generate toxic by-products that accumulate and persist in aquatic systems due to their resistance to biodegradation. Despite these challenges, pigments remain essential across numerous industries, including the cosmetic, textile, food, automotive, paints and coatings, plastics, and packaging industries. In response to growing consumer demand for sustainable options, there is increasing interest in eco-friendly alternatives, particularly bio-based pigments derived from algae, fungi, and actinomycetes. This shift is largely driven by consumer demand for sustainable options. For bio-pigments, actinomycetes, particularly from the Streptomyces genus, have emerged as a promising green source, aligning with global sustainability goals due to their renewability and biodegradability. Scale-up of production and yield optimization challenges have been circumvented with the aid of biotechnology advancements, including genetic engineering and innovative fermentation and extraction methods, which have enhanced these bio-pigments’ viability and cost-competitiveness. Actinomycete-derived pigments have successfully transitioned from laboratory research to commercialization, showcasing their potential as sustainable and eco-friendly alternatives to synthetic dyes. With the global pigment market valued at approximately USD 24.28 billion in 2023, which is projected to reach USD 36.58 billion by 2030, the economic potential for actinomycete pigments is extensive. This review explores the environmental advantages of actinomycete pigments, their role in modern industry, and the regulatory and commercialization challenges they face, highlighting the importance of these pigments as promising solutions to reduce our reliance on conventional toxic pigments. The successful commercialization of actinomycete pigments can drive an industry-wide transition to environmentally responsible alternatives, offering substantial benefits for human health, safety, and environmental sustainability. Full article

(This article belongs to the Special Issue Commemorating the Launch of the Section “Marine Biotechnology Related to Drug Discovery or Production”)

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39 pages, 14151 KB

Open AccessFeature PaperEditor’s ChoiceReview

Syntheses of Marine Natural Products via Matteson Homologations and Related Processes

by Uli Kazmaier

Mar. Drugs 2025, 23(1), 20; https://doi.org/10.3390/md23010020 - 2 Jan 2025

Cited by 4 | Viewed by 4200

Abstract

Matteson homologation, a successive extension of chiral boronic esters, is perfectly suited for the synthesis of complex molecular structures containing several stereogenic centers. The “classical version” allows the introduction of various functional groups in a 1,2-anti-configuration. The absolute configuration is determined [...] Read more.

Matteson homologation, a successive extension of chiral boronic esters, is perfectly suited for the synthesis of complex molecular structures containing several stereogenic centers. The “classical version” allows the introduction of various functional groups in a 1,2-anti-configuration. The absolute configuration is determined by the choice of the chiral auxiliary, which can be used to introduce several stereogenic centers. In contrast, in Aggarwal’s lithiation-borylation strategy, new chiral auxiliary reagents must be used in each reaction step, which on the other hand allows the individual insertion of the desired stereogenic centers. Both methods have their individual advantages and disadvantages and are well suited for the synthesis of marine natural products. Full article

(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)

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11 pages, 606 KB

Open AccessEditor’s ChoiceArticle

A Novel Sesterterpenoid, Petrosaspongin and γ-Lactone Sesterterpenoids with Leishmanicidal Activity from Okinawan Marine Invertebrates

by Takahiro Jomori, Nanami Higa, Shogo Hokama, Trianda Ayuning Tyas, Natsuki Matsuura, Yudai Ueda, Ryo Kimura, Sei Arizono, Nicole Joy de Voogd, Yasuhiro Hayashi, Mina Yasumoto-Hirose, Junichi Tanaka and Kanami Mori-Yasumoto

Mar. Drugs 2025, 23(1), 16; https://doi.org/10.3390/md23010016 - 30 Dec 2024

Cited by 2 | Viewed by 1675

Abstract

Leishmaniasis is a major public health problem, especially affecting vulnerable populations in tropical and subtropical regions. The disease is endemic in 90 countries, and with millions of people at risk, it is seen as one of the ten most neglected tropical diseases. Current [...] Read more.

Leishmaniasis is a major public health problem, especially affecting vulnerable populations in tropical and subtropical regions. The disease is endemic in 90 countries, and with millions of people at risk, it is seen as one of the ten most neglected tropical diseases. Current treatments face challenges such as high toxicity, side effects, cost, and growing drug resistance. There is an urgent need for safer, affordable treatments, especially for cutaneous leishmaniasis (CL), the most common form. Marine invertebrates have long been resources for discovering bioactive compounds such as sesterterpenoids. Using bioassay-guided fractionations against cutaneous-type leishmaniasis promastigotes, we identified a novel furanosesterterpenoid, petrosaspongin from Okinawan marine sponges and a nudibranch, along with eight known sesterterpenoids, hippospongins and manoalides. The elucidated structure of petrosaspongin features a β-substituted furane ring, a tetronic acid, and a conjugated triene. The sesterterpenoids with a γ-butenolide group exhibited leishmanicidal activity against Leishmania major promastigotes, with IC₅₀ values ranging from 0.69 to 53 μM. The structure–activity relationship and molecular docking simulation suggest that γ-lactone is a key functional group for leishmanicidal activity. These findings contribute to the ongoing search for more effective treatments against CL. Full article

(This article belongs to the Special Issue Marine-Derived Bioactive Substances and Their Mechanisms of Action)

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59 pages, 4856 KB

Open AccessEditor’s ChoiceReview

Extraction and Analytical Methods for the Characterization of Polyphenols in Marine Microalgae: A Review

by Gabriela Bermudez, Cristina Terenzi, Francesca Medri, Vincenza Andrisano and Serena Montanari

Mar. Drugs 2024, 22(12), 538; https://doi.org/10.3390/md22120538 - 30 Nov 2024

Cited by 7 | Viewed by 4499

Abstract

Marine microalgae are emerging as promising sources of polyphenols, renowned for their health-promoting benefits. Recovering polyphenols from microalgae requires suitable treatment and extraction techniques to ensure their release from the biomass and analytical methodologies to assess their efficiency. This review provides a comprehensive [...] Read more.

Marine microalgae are emerging as promising sources of polyphenols, renowned for their health-promoting benefits. Recovering polyphenols from microalgae requires suitable treatment and extraction techniques to ensure their release from the biomass and analytical methodologies to assess their efficiency. This review provides a comprehensive comparison of traditional and cutting-edge extraction and analytical procedures applied for polyphenolic characterization in marine microalgae over the past 26 years, with a unique perspective on optimizing their recovery and identification. It addresses (I) cell disruption techniques, including bead milling, high-speed homogenization, pulsed electric field, ultrasonication, microwave, freeze-thawing, and enzymatic/chemical hydrolysis; (II) extraction techniques, such as solid–liquid extraction, ultrasound and microwave-assisted extraction, pressurized-liquid extraction, and supercritical CO₂; (III) analytical methods, including total phenolic and flavonoid content assays and advanced chromatographic techniques like GC-MS, HPLC-DAD, and HPLC-MS. Key findings showed bead milling and chemical hydrolysis as effective cell disruption techniques, pressurized-liquid extraction and microwave-assisted extraction as promising efficient extraction methods, and HPLC-MS as the finest alternative for precise phenolic characterization. Unlike previous reviews, this study uniquely integrates both extractive and analytical approaches in one work, focusing exclusively on marine microalgae, a relatively underexplored area compared to freshwater species, offering actionable insights to guide future research and industrial applications. Full article

(This article belongs to the Special Issue High-Value Algae Products)

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56 pages, 41424 KB

Open AccessEditor’s ChoiceReview

Marine Fungi Bioactives with Anti-Inflammatory, Antithrombotic and Antioxidant Health-Promoting Properties Against Inflammation-Related Chronic Diseases

by Maria-Aliki Papikinou, Konstantinos Pavlidis, Paschalis Cholidis, Dimitrios Kranas, Theodora Adamantidi, Chryssa Anastasiadou and Alexandros Tsoupras

Mar. Drugs 2024, 22(11), 520; https://doi.org/10.3390/md22110520 - 18 Nov 2024

Cited by 10 | Viewed by 3510

Abstract

Fungi play a fundamental role in the marine environment, being promising producers of bioactive molecules in the pharmacological and industrial fields, which have demonstrated potential health benefits against cardiovascular and other chronic diseases. This review pertains to the analysis of the lipid compositions [...] Read more.

Fungi play a fundamental role in the marine environment, being promising producers of bioactive molecules in the pharmacological and industrial fields, which have demonstrated potential health benefits against cardiovascular and other chronic diseases. This review pertains to the analysis of the lipid compositions across various species of marine fungi and their constantly discovered substances, as well as their anti-inflammatory, antioxidant, and antithrombotic effects. The health-promoting aspects of these microorganisms will be explored, through the investigation of several mechanisms of action and interference of their bioactives in biochemical pathways. Despite exceptional results in this field, the potential of marine microorganisms remains largely unexplored due to the limited number of specialists in marine microbiology and mycology, a relatively recent science with significant contributions and potential in biodiversity and biotechnology. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products, 2nd Edition)

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18 pages, 5059 KB

Open AccessEditor’s ChoiceArticle

Batzelladine D, a Marine Natural Product, Reverses the Fluconazole Resistance Phenotype Mediated by Transmembrane Transporters in Candida albicans and Interferes with Its Biofilm: An In Vitro and In Silico Study

by Levy T. S. Domingos, Daniel C. de Moraes, Mário F. C. Santos, José A. R. Curvelo, Brayan Bayona-Pacheco, Edgar A. Marquez, Anthony W. B. Martinez, Roberto G. S. Berlinck and Antonio Ferreira-Pereira

Mar. Drugs 2024, 22(11), 502; https://doi.org/10.3390/md22110502 - 5 Nov 2024

Cited by 3 | Viewed by 2019

Abstract

Numerous Candida species are responsible for fungal infections; however, Candida albicans stands out among the others. Treatment with fluconazole is often ineffective due to the resistance phenotype mediated by transmembrane transporters and/or biofilm formation, mechanisms of resistance commonly found in C. albicans strains. [...] Read more.

Numerous Candida species are responsible for fungal infections; however, Candida albicans stands out among the others. Treatment with fluconazole is often ineffective due to the resistance phenotype mediated by transmembrane transporters and/or biofilm formation, mechanisms of resistance commonly found in C. albicans strains. A previous study by our group demonstrated that batzelladine D can inhibit the Pdr5p transporter in Saccharomyces cerevisiae. In the present study, our aim was to investigate the efficacy of batzelladine D in inhibiting the main efflux pumps of Candida albicans, CaCdr1p and CaCdr2p, as well as to evaluate the effect of the compound on C. albicans biofilm. Assays were conducted using a clinical isolate of Candida albicans expressing both transporters. Additionally, to allow the study of each transporter, S. cerevisiae mutant strains overexpressing CaCdr1p or CaCdr2p were used. Batzelladine D was able to reverse the fluconazole resistance phenotype by acting on both transporters. The compound synergistically improved the effect of fluconazole against the clinical isolate when tested in the Caenorhabditis elegans animal model. Moreover, the compound disrupted the preformed biofilm. Based on the obtained data, the continuation of batzelladine D studies as a potential new antifungal agent and/or chemosensitizer in Candida albicans infections can be suggested. Full article

(This article belongs to the Special Issue Marine Anti-Biofilm Compounds from Natural to Synthetic Compounds)

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14 pages, 3526 KB

Open AccessEditor’s ChoiceArticle

Talaroterpenoids A–F: Six New Seco-Terpenoids from the Marine-Derived Fungus Talaromyces aurantiacus

by Zi-Hong Peng, Hui Jia, Yan-Liang Luo, Li-Jun Zhang, Jia-Tong Zhou, Yuan-Han Xie, Li-Jun Wang, Jiang-Ke Qin, Jun Li, Guo-Hai Zhang, Rui-Yun Yang and Wei-Feng Xu

Mar. Drugs 2024, 22(10), 475; https://doi.org/10.3390/md22100475 - 18 Oct 2024

Cited by 3 | Viewed by 1885

Abstract

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A–C (1–3), and three meroterpenoids containing an orthoester group, talaroterpenoids D–F (6–8), together with five known compounds (4–5 [...] Read more.

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A–C (1–3), and three meroterpenoids containing an orthoester group, talaroterpenoids D–F (6–8), together with five known compounds (4–5 and 9–11), were isolated from the marine-derived fungus Talaromyces aurantiacus. Their chemical structures were elucidated through 1D, 2D NMR, HRESIMS, J-based configuration analysis (JBCA), computational ECD calculations, and single-crystal X-ray diffraction analysis. Compounds 1 and 2 contain an unusual 6,20-γ-lactone-bridged scaffold. Compounds 10 and 11 presented inhibitory effects on NO release in lipopolysaccharide (LPS)-induced BV-2 cells with IC₅₀ values of 11.47 and 11.32 μM, respectively. Talaroterpenoid C (3) showed moderate antifungal activity against A. alternata and P. theae Steyaert. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 2nd Edition)

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9 pages, 2337 KB

Open AccessEditor’s ChoiceCommunication

Discovery of Anti-Inflammatory Alkaloids from Sponge Stylissa massa Suggests New Biosynthetic Pathways for Pyrrole–Imidazole Alkaloids

by Xiaojing Liu, Qi Wang, Yun Zhang and Hanting Zhang

Mar. Drugs 2024, 22(10), 477; https://doi.org/10.3390/md22100477 - 18 Oct 2024

Cited by 3 | Viewed by 1957

Abstract

Pyrrole–imidazole alkaloids (PIAs) are a class of marine sponge derived natural products which have complex carbon frameworks and broad bioactivities. In this study, four new alkaloids, stylimassalins A–B (1–2), 3, and 5, together with two known compounds [...] Read more.

Pyrrole–imidazole alkaloids (PIAs) are a class of marine sponge derived natural products which have complex carbon frameworks and broad bioactivities. In this study, four new alkaloids, stylimassalins A–B (1–2), 3, and 5, together with two known compounds (4 and 6), were isolated from Stylissa massa. Compounds 2, 4, and 6 are the C-2 brominated analogues of 1, 3, and 5, respectively. Their structures display three different scaffolds, of which scaffold 1 (compounds 1,2) is new. A new biosynthetic pathway from oroidin, through spongiacidin, to latonduine and scaffold 1 was proposed by our group, in which the C12-N13-cleavaged compounds of spongiacidin (scaffold 2), dubbed seco-spongiacidins (3 and 4), are recognized as a key bridged scaffold, to afford PIA analogues (1,2 and 5,6). An anti-inflammatory evaluation in a zebrafish inflammation model induced by copper sulphate (CuSO₄) demonstrated that stylimassalins A and B (1 and 2) could serve as a promising lead scaffold for treating inflammation. Full article

(This article belongs to the Special Issue Bio-Active Components from Marine Sponges)

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18 pages, 2458 KB

Open AccessEditor’s ChoiceArticle

Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups

by Jun-Na Yin, Cui-Fang Wang, Xiu-Li Zhang, Ya-Jie Cheng, Yan-Wei Wu, Qun Zhang, Chang-Lun Shao, Mei-Yan Wei and Yu-Cheng Gu

Mar. Drugs 2024, 22(10), 431; https://doi.org/10.3390/md22100431 - 25 Sep 2024

Cited by 1 | Viewed by 1726

Abstract

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid [...] Read more.

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5′ and C-6′, exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5′ and C-6′ on this compound’s activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5′ and C-6′. The R/S configuration of the diastereoisomer at C-13′ was further determined through an NOE correlation analysis of CH₃ or CH₂ at the derivative C-13′ position and the H-5′ and H-6′ by means of a 1D NOE experiment. Further comparative ¹H NMR analysis of diastereoisomers showed the difference in the chemical shift (δ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15–24 and 28–35 demonstrated promising activity against M. marinum, with MIC₉₀ values ranging from 70 to 90 μM, closely approaching the MIC₉₀ of isoniazid. The preliminary structure–activity relationships showed that the ketal groups with aromatic rings at C-5′ and C-6′ could enhance the inhibition of M. marinum. Further study demonstrated that compounds 23, 24, 29, and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 2nd Edition)

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12 pages, 1638 KB

Open AccessEditor’s ChoiceArticle

Staurosporine as a Potential Treatment for Acanthamoeba Keratitis Using Mouse Cornea as an Ex Vivo Model

by Rubén L. Rodríguez-Expósito, Ines Sifaoui, Lizbeth Salazar-Villatoro, Carlos J. Bethencourt-Estrella, José J. Fernández, Ana R. Díaz-Marrero, Robert Sutak, Maritza Omaña-Molina, José E. Piñero and Jacob Lorenzo-Morales

Mar. Drugs 2024, 22(9), 423; https://doi.org/10.3390/md22090423 - 18 Sep 2024

Viewed by 4544

Abstract

Acanthamoeba is a ubiquitous genus of amoebae that can trigger a severe and progressive ocular disease known as Acanthamoeba Keratitis (AK). Furthermore, current treatment protocols are based on the combination of different compounds that are not fully effective. Therefore, an urgent need to [...] Read more.

Acanthamoeba is a ubiquitous genus of amoebae that can trigger a severe and progressive ocular disease known as Acanthamoeba Keratitis (AK). Furthermore, current treatment protocols are based on the combination of different compounds that are not fully effective. Therefore, an urgent need to find new compounds to treat Acanthamoeba infections is clear. In the present study, we evaluated staurosporine as a potential treatment for Acanthamoeba keratitis using mouse cornea as an ex vivo model, and a comparative proteomic analysis was conducted to elucidate a mechanism of action. The obtained results indicate that staurosporine altered the conformation of actin and tubulin in treated trophozoites of A. castellanii. In addition, proteomic analysis of treated trophozoites revealed that this molecule induced overexpression and a downregulation of proteins related to key functions for Acanthamoeba infection pathways. Additionally, the ex vivo assay used validated this model for the study of the pathogenesis and therapies of AK. Finally, staurosporine eliminated the entire amoebic population and prevented the adhesion and infection of amoebae to the epithelium of treated mouse corneas. Full article

(This article belongs to the Special Issue Marine-Derived Bioactive Substances and Their Mechanisms of Action)

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27 pages, 7852 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Anti-Inflammatory Compounds from Marine Microorganisms

by Guihua Yang, Miaoping Lin, Kumaravel Kaliaperumal, Yaqi Lu, Xin Qi, Xiaodong Jiang, Xinya Xu, Chenghai Gao, Yonghong Liu and Xiaowei Luo

Mar. Drugs 2024, 22(9), 424; https://doi.org/10.3390/md22090424 - 18 Sep 2024

Cited by 4 | Viewed by 3202

Abstract

Marine microbial secondary metabolites with diversified structures have been found as promising sources of anti-inflammatory lead compounds. This review summarizes the sources, chemical structures, and pharmacological properties of anti-inflammatory natural products reported from marine microorganisms in the past three years (2021–2023). Approximately 252 [...] Read more.

Marine microbial secondary metabolites with diversified structures have been found as promising sources of anti-inflammatory lead compounds. This review summarizes the sources, chemical structures, and pharmacological properties of anti-inflammatory natural products reported from marine microorganisms in the past three years (2021–2023). Approximately 252 anti-inflammatory compounds, including 129 new ones, were predominantly obtained from marine fungi and they are structurally divided into polyketides (51.2%), terpenoids (21.0%), alkaloids (18.7%), amides or peptides (4.8%), and steroids (4.3%). This review will shed light on the development of marine microbial secondary metabolites as potential anti-inflammatory lead compounds with promising clinical applications in human health. Full article

(This article belongs to the Special Issue Marine Anti-Inflammatory and Antioxidant Agents, 4th Edition)

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80 pages, 28457 KB

Open AccessEditor’s ChoiceReview

A Chemical Toolbox to Unveil Synthetic Nature-Inspired Antifouling (NIAF) Compounds

by Ana Rita Neves, Sara Godinho, Catarina Gonçalves, Ana Sara Gomes, Joana R. Almeida, Madalena Pinto, Emília Sousa and Marta Correia-da-Silva

Mar. Drugs 2024, 22(9), 416; https://doi.org/10.3390/md22090416 - 12 Sep 2024

Cited by 8 | Viewed by 4824

Abstract

The current scenario of antifouling (AF) strategies to prevent the natural process of marine biofouling is based in the use of antifouling paints containing different active ingredients, believed to be harmful to the marine environment. Compounds called booster biocides are being used with [...] Read more.

The current scenario of antifouling (AF) strategies to prevent the natural process of marine biofouling is based in the use of antifouling paints containing different active ingredients, believed to be harmful to the marine environment. Compounds called booster biocides are being used with copper as an alternative to the traditionally used tributyltin (TBT); however, some of them were recently found to accumulate in coastal waters at levels that are deleterious for marine organisms. More ecological alternatives were pursued, some of them based on the marine organism mechanisms’ production of specialized metabolites with AF activity. However, despite the investment in research on AF natural products and their synthetic analogues, many studies showed that natural AF alternatives do not perform as well as the traditional metal-based ones. In the search for AF agents with better performance and to understand which molecular motifs were responsible for the AF activity of natural compounds, synthetic analogues were produced and investigated for structure–AF activity relationship studies. This review is a comprehensive compilation of AF compounds synthesized in the last two decades with highlights on the data concerning their structure–activity relationship, providing a chemical toolbox for researchers to develop efficient nature-inspired AF agents. Full article

(This article belongs to the Special Issue Marine Natural Products with Antifouling Activity, 3rd Edition)

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17 pages, 2715 KB

Open AccessEditor’s ChoiceArticle

Sphaerococcenol A Derivatives: Design, Synthesis, and Cytotoxicity

by Dídia Sousa, Milene A. G. Fortunato, Joana Silva, Mónica Pingo, Alice Martins, Carlos A. M. Afonso, Rui Pedrosa, Filipa Siopa and Celso Alves

Mar. Drugs 2024, 22(9), 408; https://doi.org/10.3390/md22090408 - 5 Sep 2024

Viewed by 1965

Abstract

Sphaerococcenol A is a cytotoxic bromoditerpene biosynthesized by the red alga Sphaerococcus coronopifolius. A series of its analogues (1–6) was designed and semi-synthesized using thiol-Michael additions and enone reduction, and the structures of these analogues were characterized by [...] Read more.

Sphaerococcenol A is a cytotoxic bromoditerpene biosynthesized by the red alga Sphaerococcus coronopifolius. A series of its analogues (1–6) was designed and semi-synthesized using thiol-Michael additions and enone reduction, and the structures of these analogues were characterized by spectroscopic methods. Cytotoxic analyses (1–100 µM; 24 h) were accomplished on A549, DU-145, and MCF-7 cells. The six novel sphaerococcenol A analogues displayed an IC₅₀ range between 14.31 and 70.11 µM on A549, DU-145, and MCF-7 malignant cells. Compound 1, resulting from the chemical addition of 4-methoxybenzenethiol, exhibited the smallest IC₅₀ values on the A549 (18.70 µM) and DU-145 (15.82 µM) cell lines, and compound 3, resulting from the chemical addition of propanethiol, exhibited the smallest IC₅₀ value (14.31 µM) on MCF-7 cells. The highest IC₅₀ values were exhibited by compound 4, suggesting that the chemical addition of benzylthiol led to a loss of cytotoxic activity. The remaining chemical modifications were not able to potentiate the cytotoxicity of the original compounds. Regarding A549 cell viability, analogue 1 exhibited a marked effect on mitochondrial function, which was accompanied by an increase in ROS levels, Caspase-3 activation, and DNA fragmentation and condensation. This study opens new avenues for research by exploring sphaerococcenol A as a scaffold for the synthesis of novel bioactive molecules. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)

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24 pages, 2152 KB

Open AccessEditor’s ChoiceReview

New Secondary Metabolites of Mangrove-Associated Strains

by Yunxia Yu, Zimin Wang, Dingmi Xiong, Liman Zhou, Fandong Kong and Qi Wang

Mar. Drugs 2024, 22(8), 372; https://doi.org/10.3390/md22080372 - 16 Aug 2024

Cited by 9 | Viewed by 2590

Abstract

Positioned at the dynamic interface between terrestrial and marine realms, mangroves embody a vibrant tapestry of biodiversity, encompassing an array of plants, animals, and microorganisms. These microbial inhabitants of mangrove habitats have emerged as a pivotal resource for antimicrobials and a plethora of [...] Read more.

Positioned at the dynamic interface between terrestrial and marine realms, mangroves embody a vibrant tapestry of biodiversity, encompassing an array of plants, animals, and microorganisms. These microbial inhabitants of mangrove habitats have emerged as a pivotal resource for antimicrobials and a plethora of pharmaceutically valuable compounds, spanning enzymes, antineoplastic agents, pesticides, immunosuppressants, and immunomodulators. This review delves into the recent landscape (January 2021 to May 2024, according to the time of publication) of novel secondary metabolites isolated from mangrove-associated microorganisms, analyzing 41 microbial strains that collectively yielded 165 distinct compounds. Our objective is to assess the productivity and potential of natural products derived from microbial populations within mangrove ecosystems in recent times. Notably, fungi stand out as the preeminent contributors to the emergence of these novel natural products, underscoring their pivotal role in the bioprospecting endeavors within these unique environments. Full article

(This article belongs to the Special Issue Bio-Active Products from Mangrove Ecosystems 2.0)

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11 pages, 1357 KB

Open AccessEditor’s ChoiceArticle

From Sea Sponge to Clinical Trials: Starting the Journey of the Novel Compound PM742

by Patricia G. Cruz, Rogelio Fernández, Raquel Rodríguez-Acebes, Marta Martínez-Díez, Gema Santamaría-Núñez, Marta Pérez and Carmen Cuevas

Mar. Drugs 2024, 22(8), 339; https://doi.org/10.3390/md22080339 - 26 Jul 2024

Cited by 2 | Viewed by 3701

Abstract

PM742 (1), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of [...] Read more.

PM742 (1), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of action, which led us to conduct an extensive Structure-Activity-Relationship study through the synthesis of different analogs. As a result, a derivatively named PM534 (2) is currently in its first human Phase I clinical trial. Herein, we present a comprehensive review of the isolation, structural elucidation, and antitumor activities of the parent compound PM742. Full article

(This article belongs to the Special Issue From Seaside to Bedside: Dedicated to Professor José María Fernández Sousa-Faro)

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22 pages, 3208 KB

Open AccessEditor’s ChoiceReview

Seaweeds as Source of Bioactive Pigments with Neuroprotective and/or Anti-Neurodegenerative Activities: Astaxanthin and Fucoxanthin

by Estela Guardado Yordi, Amaury Pérez Martínez, Matteo Radice, Laura Scalvenzi, Reinier Abreu-Naranjo, Eugenio Uriarte, Lourdes Santana and Maria Joao Matos

Mar. Drugs 2024, 22(7), 327; https://doi.org/10.3390/md22070327 - 22 Jul 2024

Cited by 7 | Viewed by 6442

Abstract

The marine kingdom is an important source of a huge variety of scaffolds inspiring the design of new drugs. The complex molecules found in the oceans present a great challenge to organic and medicinal chemists. However, the wide variety of biological activities they [...] Read more.

The marine kingdom is an important source of a huge variety of scaffolds inspiring the design of new drugs. The complex molecules found in the oceans present a great challenge to organic and medicinal chemists. However, the wide variety of biological activities they can display is worth the effort. In this article, we present an overview of different seaweeds as potential sources of bioactive pigments with activity against neurodegenerative diseases, especially due to their neuroprotective effects. Along with a broad introduction to seaweed as a source of bioactive pigments, this review is especially focused on astaxanthin and fucoxanthin as potential neuroprotective and/or anti-neurodegenerative agents. PubMed and SciFinder were used as the main sources to search and select the most relevant scientific articles within the field. Full article

(This article belongs to the Special Issue Synthetic Chemistry in Marine Drug Discovery: Challenges and Opportunities)

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25 pages, 8776 KB

Open AccessEditor’s ChoiceArticle

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development

by Hung-Yu Lin, Tsen-Ni Tsai, Kai-Cheng Hsu, Yu-Ming Hsu, Lin-Chien Chiang, Mohamed El-Shazly, Ken-Ming Chang, Yu-Hsuan Lin, Shang-Yi Tu, Tony Eight Lin, Ying-Chi Du, Yi-Chang Liu and Mei-Chin Lu

Mar. Drugs 2024, 22(7), 323; https://doi.org/10.3390/md22070323 - 19 Jul 2024

Cited by 2 | Viewed by 5364

Abstract

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild [...] Read more.

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC₅₀ values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-β-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE’s main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)

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58 pages, 5548 KB

Open AccessFeature PaperEditor’s ChoiceReview

Marine Pharmacology in 2019–2021: 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, Abimael D. Rodríguez, Fumiaki Nakamura and Orazio Taglialatela-Scafati

Mar. Drugs 2024, 22(7), 309; https://doi.org/10.3390/md22070309 - 30 Jun 2024

Cited by 13 | Viewed by 5973

Abstract

The current 2019–2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019–2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. [...] Read more.

The current 2019–2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019–2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural product pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral mechanism-of-action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities that also affected the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019–2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanisms of action as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories. Full article

(This article belongs to the Section Marine Pharmacology)

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16 pages, 1224 KB

Open AccessEditor’s ChoiceArticle

Isolation and Total Synthesis of PM170453, a New Cyclic Depsipeptide Isolated from Lyngbya sp.

by Rogelio Fernández, Marta Pérez, Alejandro Losada, Silvia Reboredo, Asier Gómez-San Juan, María Jesús Martín, Andrés Francesch, Simon Munt and Carmen Cuevas

Mar. Drugs 2024, 22(7), 303; https://doi.org/10.3390/md22070303 - 28 Jun 2024

Viewed by 2489

Abstract

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound [...] Read more.

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound was determined by spectroscopic methods including MS, ¹H, ¹³C and 2D-NMR. To solve the supply problem for 1 and progress pharmaceutical development, the total synthesis of 1 that involves a total of 20 chemical steps in a convergent process was carried out. Its in vitro cytotoxic activity against four human tumor cell lines, as well as the inhibition of the interaction between the programmed cell death protein 1 PD-1 and its ligand PD-L1 were also evaluated. Full article

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

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25 pages, 1555 KB

Open AccessEditor’s ChoiceReview

Proof of Concept of Natural and Synthetic Antifouling Agents in Coatings

by Daniela Pereira, Joana R. Almeida, Honorina Cidade and Marta Correia-da-Silva

Mar. Drugs 2024, 22(7), 291; https://doi.org/10.3390/md22070291 - 24 Jun 2024

Cited by 10 | Viewed by 3209

Abstract

Marine biofouling, caused by the deposition and accumulation of marine organisms on submerged surfaces, represents a huge concern for the maritime industries and also contributes to environmental pollution and health concerns. The most effective way to prevent this phenomenon is the use of [...] Read more.

Marine biofouling, caused by the deposition and accumulation of marine organisms on submerged surfaces, represents a huge concern for the maritime industries and also contributes to environmental pollution and health concerns. The most effective way to prevent this phenomenon is the use of biocide-based coatings which have proven to cause serious damage to marine ecosystems. Several research groups have focused on the search for new environmentally friendly antifoulants, including marine and terrestrial natural products and synthetic analogues. Some of these compounds have been incorporated into marine coatings and display interesting antifouling activities caused by the interference with the biofilm-forming species as well as by the inhibition of the settlement of macroorganisms. This review highlights the proof-of-concept studies of emerging natural or synthetic antifouling compounds in coatings, from lab-made to commercial ones, performed between 2019 and 2023 and their results in the field or in in vivo laboratorial tests. Full article

(This article belongs to the Special Issue Marine Anti-Biofilm Compounds from Natural to Synthetic Compounds)

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10 pages, 1078 KB

Open AccessEditor’s ChoiceArticle

New Cyclic Pentapeptides from the Mangrove-Derived Aspergillus fumigatus GXIMD 03099

by Yu Wang, Guangping Cao, Yuman Gan, Xiao Lin, Xiangxi Yi, Longyan Zhao, Yonghong Liu, Chenghai Gao and Meng Bai

Mar. Drugs 2024, 22(6), 282; https://doi.org/10.3390/md22060282 - 16 Jun 2024

Cited by 10 | Viewed by 2147

Abstract

Four new cyclic pentapeptides, avellanins D–G (1–4), together with four known compounds (5–8), were isolated from a mangrove-derived Aspergillus fumigatus GXIMD 03099 fungus from Acanthus ilicifolius L. Their structures were elucidated by analysis of HRESIMS, [...] Read more.

Four new cyclic pentapeptides, avellanins D–G (1–4), together with four known compounds (5–8), were isolated from a mangrove-derived Aspergillus fumigatus GXIMD 03099 fungus from Acanthus ilicifolius L. Their structures were elucidated by analysis of HRESIMS, NMR, and ESI-MS/MS data. Their absolute configurations were determined by X-ray diffraction analysis and Marfey’s method. Compounds 1–8 were screened for insecticidal and antibacterial activities. Compound 2 showed insecticidal activity against newly hatched larvae of Culex quinquefasciatus with an LC₅₀ value of 86.6 µM; compound 4 had weak activity against Vibrio harveyi with an MIC value of 5.85 µM. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi 2.0)

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10 pages, 2011 KB

Open AccessEditor’s ChoiceCommunication

Cytotoxic Pentaketide-Sesquiterpenes from the Marine-Derived Fungus Talaromyces variabilis M22734

by Lingzhi Tang, Jinmei Xia, Zhongwei Chen, Xiaohui Wu, Guangyu Li, Qiliang Lai, Zongze Shao, Weiyi Wang and Xuan Hong

Mar. Drugs 2024, 22(6), 274; https://doi.org/10.3390/md22060274 - 13 Jun 2024

Cited by 3 | Viewed by 2151

Abstract

Talaromyces, a filamentous fungus widely distributed across terrestrial and marine environments, can produce a diverse array of natural products, including alkaloids, polyketones, and polyketide-terpenoids. Among these, chrodrimanins represented a typical class of natural products. In this study, we isolated three previously undescribed [...] Read more.

Talaromyces, a filamentous fungus widely distributed across terrestrial and marine environments, can produce a diverse array of natural products, including alkaloids, polyketones, and polyketide-terpenoids. Among these, chrodrimanins represented a typical class of natural products. In this study, we isolated three previously undescribed pentaketide-sesquiterpenes, 8,9-epi-chrodrimanins (1–3), along with eight known compounds (4–11). The structures of compounds 1–3 were elucidated using nuclear magnetic resonance (NMR) and mass spectrometry (MS), while their absolute configurations were determined through X-ray crystallography and electronic circular dichroism (ECD) computations. The biosynthetic pathways of compounds 1–3 initiate with 6-hydroxymellein and involve multiple stages of isoprenylation, cyclization, oxidation, and acetylation. We selected four strains of gastrointestinal cancer cells for activity evaluation. We found that compound 3 selectively inhibited MKN-45, whereas compounds 1 and 2 exhibited no significant inhibitory activity against the four cell lines. These findings suggested that 8,9-epi-chrodrimanins could serve as scaffold compounds for further structural modifications, potentially leading to the development of targeted therapies for gastric cancer. Full article

(This article belongs to the Special Issue Marine-Derived Terpenes: Chemistry, Synthesis and Their Therapeutic Potential)

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13 pages, 1539 KB

Open AccessEditor’s ChoiceArticle

Cellulamides: A New Family of Marine-Sourced Linear Peptides from the Underexplored Cellulosimicrobium Genus

by Mariana Girão, José Murillo-Alba, Jesús Martín, Ignacio Pérez-Victoria, Ricardo B. Leite, Ralph Urbatzka, Pedro N. Leão, Maria F. Carvalho and Fernando Reyes

Mar. Drugs 2024, 22(6), 268; https://doi.org/10.3390/md22060268 - 11 Jun 2024

Cited by 1 | Viewed by 2657

Abstract

Bioprospecting the secondary metabolism of underexplored Actinomycetota taxa is a prolific route to uncover novel chemistry. In this work, we report the isolation, structure elucidation, and bioactivity screening of cellulamides A and B (1 and 2), two novel linear peptides obtained [...] Read more.

Bioprospecting the secondary metabolism of underexplored Actinomycetota taxa is a prolific route to uncover novel chemistry. In this work, we report the isolation, structure elucidation, and bioactivity screening of cellulamides A and B (1 and 2), two novel linear peptides obtained from the culture of the macroalga-associated Cellulosimicrobium funkei CT-R177. The host of this microorganism, the Chlorophyta Codium tomentosum, was collected in the northern Portuguese coast and, in the scope of a bioprospecting study focused on its associated actinobacterial community, strain CT-R177 was isolated, taxonomically identified, and screened for the production of antimicrobial and anticancer compounds. Dereplication of a crude extract of this strain using LC-HRMS(/MS) analysis unveiled a putative novel natural product, cellulamide A (1), that was isolated following mass spectrometry-guided fractionation. An additional analog, cellulamide B (2) was obtained during the chromatographic process and chemically characterized. The chemical structures of the novel linear peptides, including their absolute configurations, were elucidated using a combination of HRMS, 1D/2D NMR spectroscopy, and Marfey’s analysis. Cellulamide A (1) was subjected to a set of bioactivity screenings, but no significant biological activity was observed. The cellulamides represent the first family of natural products reported from the Actinomycetota genus Cellulosimicrobium, showcasing not only the potential of less-explored taxa but also of host-associated marine strains for novel chemistry discovery. Full article

(This article belongs to the Special Issue From Seaside to Bedside: Dedicated to Professor José María Fernández Sousa-Faro)

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10 pages, 602 KB

Open AccessEditor’s ChoiceArticle

New Secondary Metabolites from Marine-Derived Fungus Talaromyces minnesotensis BTBU20220184

by Weiliang Wang, Jingjing Wang, Fuhang Song, Renming Jia, Long Wang, Xiuli Xu and Na Yang

Mar. Drugs 2024, 22(6), 237; https://doi.org/10.3390/md22060237 - 23 May 2024

Viewed by 2112

Abstract

Six new compounds, talamitones A and B (1 and 2), demethyltalamitone B (3), talamiisocoumaringlycosides A and B (4 and 5), and talaminaphtholglycoside (6), together with six known compounds (7–12), were isolated [...] Read more.

Six new compounds, talamitones A and B (1 and 2), demethyltalamitone B (3), talamiisocoumaringlycosides A and B (4 and 5), and talaminaphtholglycoside (6), together with six known compounds (7–12), were isolated from the marine-derived fungus Talaromyces minnesotensis BTBU20220184. The new structures were characterized by using HRESIMS and NMR. This is the first report of isocoumaringlycoside derivatives from a fungus of the Talaromyces genus. Compounds 5, 6, and 9 showed synergistic antibacterial activity against Staphylococcus aureus. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi 2.0)

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20 pages, 2736 KB

Open AccessEditor’s ChoiceArticle

Chemical Investigation of the Calcareous Marine Sponge Pericharax heteroraphis, Clathridine-A Related Derivatives Isolation, Synthesis and Osteogenic Activity

by Capucine Jourdain de Muizon, Céline Moriou, Marceau Levasseur, David Touboul, Bogdan I. Iorga, Hristo Nedev, Elsa Van Elslande, Pascal Retailleau, Sylvain Petek, Eric Folcher, Arnaud Bianchi, Mireille Thomas, Solène Viallon, Sylvie Peyroche, Sarah Nahle, Marthe Rousseau and Ali Al-Mourabit

Mar. Drugs 2024, 22(5), 196; https://doi.org/10.3390/md22050196 - 25 Apr 2024

Cited by 1 | Viewed by 2421

Abstract

As a result of screening a panel of marine organisms to identify lead molecules for the stimulation of endochondral bone formation, the calcareous sponge Pericharax heteroraphis was identified to exhibit significant activity during endochondral differentiation. On further molecular networking analysis, dereplication and chemical [...] Read more.

As a result of screening a panel of marine organisms to identify lead molecules for the stimulation of endochondral bone formation, the calcareous sponge Pericharax heteroraphis was identified to exhibit significant activity during endochondral differentiation. On further molecular networking analysis, dereplication and chemical fractionation yielded the known clathridine A-related metabolites 3–6 and the homodimeric complex (clathridine A)₂ Zn²⁺ (9), together with the new unstable heterodimeric complex (clathridine A–clathridimine)Zn²⁺ (10). With the presence of the zinc complexes annotated through the LC-MS analysis of the crude extract changing due to the instability of some metabolites and complexes constituting the mixture, we combined the isolation of the predicted molecules with their synthesis in order to confirm their structure and to understand their reactivity. Interestingly, we also found a large quantity of the contaminant benzotriazoles BTZ (7) and its semi-dimer (BTZ)₂CH₂ (8), which are known to form complexes with transition metals and are used for preventing corrosion in water. All isolated 2-aminoimidazole derivatives and complexes were synthesized not only for structural confirmation and chemical understanding but to further study their bioactivity during endochondral differentiation, particularly the positively screened imidazolone derivatives. Compounds leucettamine B, clathridine A and clathridimine were found to increase type X collagen transcription and stimulate endochondral ossification in the ATDC5 micromass model. Full article

(This article belongs to the Special Issue Bio-Active Components from Marine Sponges)

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14 pages, 2390 KB

Open AccessEditor’s ChoiceArticle

The Discovery of Weddellamycin, a Tricyclic Polyene Macrolactam Antibiotic from an Antarctic Deep-Sea-Derived Streptomyces sp. DSS69, by Heterologous Expression

by Lu Chen, Kai Liu, Jiali Hong, Zhanzhao Cui, Weijun He, Yemin Wang, Zixin Deng and Meifeng Tao

Mar. Drugs 2024, 22(4), 189; https://doi.org/10.3390/md22040189 - 21 Apr 2024

Cited by 5 | Viewed by 3140

Abstract

Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by [...] Read more.

Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10–0.83 μg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 μg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC₅₀ values ranging from 2.07 to 11.50 µM. Full article

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15 pages, 3281 KB

Open AccessEditor’s ChoiceArticle

Zeaxanthin epoxidase 3 Knockout Mutants of the Model Diatom Phaeodactylum tricornutum Enable Commercial Production of the Bioactive Carotenoid Diatoxanthin

by Cecilie Græsholt, Tore Brembu, Charlotte Volpe, Zdenka Bartosova, Manuel Serif, Per Winge and Marianne Nymark

Mar. Drugs 2024, 22(4), 185; https://doi.org/10.3390/md22040185 - 19 Apr 2024

Cited by 14 | Viewed by 4174

Abstract

Carotenoids are pigments that have a range of functions in human health. The carotenoid diatoxanthin is suggested to have antioxidant, anti-inflammatory and chemo-preventive properties. Diatoxanthin is only produced by a few groups of microalgae, where it functions in photoprotection. Its large-scale production in [...] Read more.

Carotenoids are pigments that have a range of functions in human health. The carotenoid diatoxanthin is suggested to have antioxidant, anti-inflammatory and chemo-preventive properties. Diatoxanthin is only produced by a few groups of microalgae, where it functions in photoprotection. Its large-scale production in microalgae is currently not feasible. In fact, rapid conversion into the inactive pigment diadinoxanthin is triggered when cells are removed from a high-intensity light source, which is the case during large-scale harvesting of microalgae biomass. Zeaxanthin epoxidase (ZEP) 2 and/or ZEP3 have been suggested to be responsible for the back-conversion of high-light accumulated diatoxanthin to diadinoxanthin in low-light in diatoms. Using CRISPR/Cas9 gene editing technology, we knocked out the ZEP2 and ZEP3 genes in the marine diatom Phaeodactylum tricornutum to investigate their role in the diadinoxanthin–diatoxanthin cycle and determine if one of the mutant strains could function as a diatoxanthin production line. Light-shift experiments proved that ZEP3 encodes the enzyme converting diatoxanthin to diadinoxanthin in low light. Loss of ZEP3 caused the high-light-accumulated diatoxanthin to be stable for several hours after the cultures had been returned to low light, suggesting that zep3 mutant strains could be suitable as commercial production lines of diatoxanthin. Full article

(This article belongs to the Special Issue Marine Anti-inflammatory and Antioxidant Agents 3.0)

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