Correction: Potentiality of Marine Microbial Metabolites in the Remedy of Alzheimer’s Disease: A Comprehensive Review

Isolation of diverse chemical compounds from marine organisms implies a promising source of natural products. Oceans cover nearly 70% of the earth’s surface and over 90% of the volume of its crust (1). Marine environment contains a variety of species, many of which have no terrestrial counterparts. Recently, trends in search of new drugs emphasize that marine microorganisms could be potential productive sources of novel secondary metabolites (2). Marine microbial secondary metabolites with chemical diversity and varied bioactivities are gaining wide applications in pharmaceutical and agricultural research (3). Their survival in extreme habitats enables marine microorganisms to develop unique physiological as well as metabolic capabilities, which may not be produced by their terrestrial counterparts. It is reported that the number of bioactive metabolites from marine microorganisms has exponentially increased during the last three decades (4). This diversity has attracted scientists to screen these products to find new medications. Bioactivity profiles of marine metabolites include neurotoxic, antiviral, antitumor, antimicrobial or cytotoxic properties and are of considerable biotechnological interest. So far, more than 30 compounds are in clinical or preclinical trials. Currently, 16 of 20 marine antitumor compounds under clinical trial are derived from microbial sources (5). A few examples are didemnin B (Aplidine™) and thiocoraline used for the treatment of different cancers (6). However, despite interest on metabolites from marine derived microorganisms, researchers encounter some problems; for example, in the study of marine bacteria, only 5% of the marine bacteria observed in marine samples were amenable to be cultured with normal microbiological techniques (7). Moreover, taxonomy of marine bacteria is very poorly defined and fermentation yields are very low and may fall in the range of milligrams per liter in some cases. Nevertheless, criteria separating marine microorganisms from their terrestrial counterparts are not ambiguous; traits that help define some of the more distinct marine microorganisms are their ability to display barophily, halophily and autotrophic growth properties. Moreover, a way essential to distinguish marine and terrestrial microbes is using 16S ribosomal RNA analysis (16S rRNA). Fortunately, microbiologists developed PCR-based screening assays that may increase the screening efficiency for bioactive compounds. In addition, advancement in the knowledge of genes involved in the biosynthesis of secondary metabolites and the knowledge with different biosynthetic systems, allow completely new approaches, such as combinatorial biosynthesis, to discover novel antibiotics and add another source of data for elucidation of metabolites structure (8). Some novel compounds from marine microorganisms are under investigation in preclinical/clinical trials. It appears that marine microbial natural products are going to be the most promising and endless source of drug development. In addition to the aforementioned methods, other innovative approaches such as ribosome engineering and the one strain and many compounds method (OSMAC), would also strongly support marine microbial natural products development. It is believed that marine microbial natural products can be better understood and discovered in the next decade by a combination of both conventional and innovative approaches (9).

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.

Marine microorganisms are increasingly recognized as primary producers of marine secondary metabolites, drawing growing research interest. Many of these organisms are unculturable, posing challenges for study. Metagenomic techniques enable research on these unculturable microorganisms, identifying various biosynthetic gene clusters (BGCs) related to marine microbial secondary metabolites, thereby unveiling their secrets. This review comprehensively analyses metagenomic methods used in discovering marine microbial secondary metabolites, highlighting tools commonly employed in BGC identification, and discussing the potential and challenges in this field. It emphasizes the key role of metagenomics in unveiling secondary metabolites, particularly in marine sponges and tunicates. The review also explores current limitations in studying these metabolites through metagenomics, noting how long-read sequencing technologies and the evolution of computational biology tools offer more possibilities for BGC discovery. Furthermore, the development of synthetic biology allows experimental validation of computationally identified BGCs, showcasing the vast potential of metagenomics in mining marine microbial secondary metabolites.

Antiviral potential of natural products from marine microbes.

The ocean is a great reservoir of biodiversity and microbial metabolites. Enzymes from marine source have recently gained considerable attention as they have lower side effects and more potency when compared to other existing sources. Fibrinolytic enzymes from microbial sources possess ability to dissolve clots and help to circumvent cardiovascular problems in more efficient and safer way. The complexity of the marine environment involves high salinity, high pressure, low temperature, special lighting conditions. This contributes to the significant differences between the enzymes generated by marine microorganisms and homologous enzymes from terrestrial microorganisms leading to the boosted marine microbial enzyme technology. Further, it is believed that sea water, which is saline in nature and chemically closer to the human blood plasma, could provide biomolecules, in particular enzymes that could have lower or no toxicity or side effects when used for therapeutic applications. However, only a small proportion of fibrinolytic enzymes from marine microbiota has been examined and an even smaller proportion has been exploited. Therefore, much work needs to be done intensively and extensively in terms of potent fibrinolytic enzymes from marine resources.

Siderophores are classically understood as microbial iron-acquisition metabolites: low-molecular-weight ligands secreted by bacteria to solubilize and transport Fe(III) under iron-limited conditions. In this review, we expand that paradigm by highlighting an emerging and underappreciated chemical axis—boron coordination by siderophores—that links terrestrial (soil/rhizosphere) and marine microbiomes. Across diverse bacterial taxa, siderophore production is widespread and central to competitive fitness because Fe(III) is poorly soluble and frequently sequestered in environmental or host matrices. Yet in boron-rich settings (seawater and borate-enriched soils), the same oxygen-donor architectures that support Fe(III) chelation can also engage boron chemistry. We synthesize evidence that carboxylate/α-hydroxyacid (dicitrate-type) and catecholate siderophores can form tetrahedral borate/boronate complexes, whereas hydroxamate siderophores generally lack the vicinal dianionic O,O motif required for stable boron binding. Structurally characterized examples—including vibrioferrin, rhizoferrin, and petrobactin—demonstrate that boron complexation is experimentally observable by ESI-MS and multinuclear NMR and can be modulated by pH and microenvironment. Integrating these findings with datasets on boron-tolerant bacteria, we propose that when iron is scarce and boron is available, boron–siderophore complexation becomes chemically feasible and may influence microbial physiology by altering ligand conformation, metal selectivity, and potentially extracellular signaling behavior—especially in marine systems where borate is abundant at oceanic pH. Overall, this review frames boron-binding siderophores as a cross-ecosystem phenomenon and a promising conceptual bridge between environmental boron geochemistry, microbial metal economy, and metalloid-mediated signaling.

Review: ca. 50 refs.

Exploitation of novel small molecules from natural sources such as microbial metabolites, medicinal plants, and marine invertebrates has contributed to the discovery of lead molecules for drugs as well as research tools on chemical biology. Chemical biology based on forward/reverse chemical genetics is a new paradigm that accelerates drug development and the functional analysis of genes and proteins. Moreover, novel natural products with unique structural or biological characteristics attract both chemists and biologists, thereby developing the field of chemical biology and medicinal chemistry. We have discovered several novel bioactive microbial metabolites by both in vivo cell–based phenotypic screenings and in vitro target–oriented screenings, and investigated their modes of action using a chemical genetics or a chemical genomics approach. In this review, we focus on the following topics; i) recent screening technology and the chemical library, ii) overview of bioactive natural products and semi–synthetic derivatives we have discovered, iii) chemical genetics approach for apoptosis signaling pathway, iv) chemical genomics approach for target identification of antifungal agent, and v) perspective.

Microorganisms sustain the high productivity of coral reefs and support one of the most diverse, valuable, and threatened ecosystems on Earth. Despite the importance of reef microorganisms, there is a lack of understanding about their ecology, especially on Caribbean reefs. Furthermore, the hastening degradation of reefs due to anthropogenic stressors has made it difficult to understand natural patterns in microbial communities in the context of larger-scale ecosystem changes. Using genomics and metabolomics approaches paired with biogeochemical and physicochemical measurements as well as quantification of cell abundances, this dissertation provides optimized methods for studying the coral microbiome, investigates potential interactions between corals and seawater microorganisms, measures changes in the composition and diversity of reef seawater microorganisms over different spatial and temporal scales, and provides baseline information about microbial ecology, biogeochemistry, and metabolite compositions of a protected and relatively-healthy Cuban coral reef-system to fill these critical knowledge gaps. I found that coral species and reef location influenced the composition of bacteria and archaea within the seawater surrounding coral colonies and this seawater was enriched with microbial colonization and interaction genes, providing evidence of a distinct microbial environment surrounding corals named the coral ecosphere. In a separate study, diel and daily variation superseded spatial variation in terms of influencing shifts in the microbial community. At a larger scale, seawater microbial communities collected from the protected reefsystem of Jardines de la Reina, Cuba had higher alpha diversity and community similarity, lower nutrient concentrations, and higher abundances of picocyanobacteria compared to less protected reef-systems within Los Canarreos, Cuba and the Florida Keys, U.S.A and seawater microbial communities collected from each reef-system were influenced by hydrogeography and environmental gradients. Lastly, the extracellular metabolite composition of reef seawater collected across Jardines de la Reina was highly similar, suggesting homogenous environmental and hydrogeographic conditions across these forereefs. Overall, this dissertation characterizes reef seawater microbial communities across different scales and provides novel, baseline information about a protected and understudied Cuban reef-system, offering critical information about the ecology of reef microorganisms within the Caribbean.

Context: Marine microorganisms represent a promising source of bioactive molecules for biomedical applications. Increasing scientific literature is describing novel metabolites isolated from marine microbes with attractive pharmacological properties, such as anti-inflammatory, immunomodulatory, and anticancer. Aims: To reveal a background of the main marine microbial-derived products that have been isolated and characterized, including recent examples. The main mechanisms of action of these compounds in different models are also discussed. Methods: This research was structured based on a four phases design. 1) the identification of research questions, 2) selection of relevant studies, 3) filtering of studies based on inclusion and exclusion criteria, and 4) collection and organization of the data. For the web search, were used PubMed, Web of Science, Science Direct and ProQuest. For the selection and classification of the papers was used PRISMA software. Results: A wide variety of marine microbial metabolites with important pharmacological properties have been discovered and characterized so far. The main sources of these compounds are marine actinomycetes, bacilli, fungi from Aspergillus and Penicillium genus, microalgae, and some marine symbiotic bacteria and fungi. Most of these metabolites exhibit cytotoxic, pro-apoptotic, anticancer, anti-inflammatory, and immunomodulatory activities. Complex structural moieties, such as multiple aromatic rings and heteroatoms, seem to be related to these properties. The mechanisms of action of most of these molecules target apoptosis-related proteins, enzymes, transcription factors, DNA binding proteins and some cell surface receptors. Conclusions: The marine environment offers an efficient and attractive way to obtain novel natural products. Marine microorganisms are a prolific source of new molecules and extracts with therapeutic potential in the treatment of chronic inflammatory diseases. They represent and ecofriendly and feasible option to obtain drug candidates with multiple mechanisms of action and important biomedical applications.

Marine microorganisms: An emerging avenue in modern nutraceuticals and functional foods

Marine microorganisms produce a variety of bioactive secondary metabolites, which represent a significant source of novel antibiotics. Heterologous expression is a valuable tool for discovering marine microbial secondary metabolites; however, marine-derived chassis cell is very scarce. Here, we build an efficient plug-and-play marine-derived gene clusters expression platform 1.0 (MGCEP 1.0) by the systematic engineering of the deep-sea-derived Streptomyces atratus SCSIO ZH16. For a proof of concept, four families of microbial bioactive metabolite biosynthetic gene clusters (BGCs), including alkaloids, aminonucleosides, nonribosomal peptides, and polyketides, were efficiently expressed in this platform. Moreover, 19 compounds, including two new angucycline antibiotics, were produced in MGCEP 1.0. Dynamic patterns of global biosynthetic gene expression in MGCEP 1.0 with or without a heterologous gene cluster were revealed at the transcriptome level. The platform MGCEP 1.0 provides new possibilities for expressing microbial secondary metabolites, especially of marine origin.

Microbial metabolites are an important source of tyrosinase (TYR) inhibitors because of their rich chemical diversity. However, because of the complex metabolic environment of microbial products, it is difficult to rapidly locate and identify natural TYR inhibitors. Affinity-based ligand screening is an important method for capturing active ingredients in complex samples, but ligand immobilization is an important factor affecting the screening process. In this paper, TYR was used as ligand, and the SpyTag/SpyCatcher coupling system was used to rapidly construct affinity chromatography vectors for screening TYR inhibitors and separating active components from complex samples. We successfully expressed SpyTag-TYR fusion protein and SpyCatcher protein, and incubated SpyCatcher protein with epoxy-activated agarose. The SpyTag-TYR protein was spontaneously coupled with SpyCatcher to obtain an affinity chromatography filler for immobilization of TYR, and the performance of the packaging material was characterized. Finally, compound 1 with enzyme inhibitory activity was successfully obtained from the fermentation product of marine microorganism C. Through HPLC, MS, 1H NMR and 13C NMR analyses, its structure was deduced as azelaic acid, and its activity was analyzed. The results showed that this is a feasible method for screening TYR inhibitors in complex systems.

Chagas disease is a parasitic disease with approximately 8 million people infected worldwide, presenting a limited and toxic treatment. Comprising a vast chemodiversity, microbial metabolites are among the most important sources of FDA-approved anti-infectives. In this work, the bioactivity-guided fractionation from an extract obtained from the bacterium Bacillus altitudinis, isolated from a red seaweed, afforded an antitrypanosomal alkaloid which was characterized as (R)-salsolinol by 1H NMR and HR-ESIMS analysis. (R)-Salsolinol showed a trypanocidal effect against the trypomastigotes (EC50 = 14µg/mL) and a selective activity against the intracellular amastigotes (EC50 = 19µg/mL), with no mammalian cytotoxicity in human monocytic cells THP-1 (CC50 >36µg/mL). In silico studies predicted a high permeability into cell membranes, as well as a high gastrointestinal absorption, with acceptable parameters in pharmaceutical filters, as well as cruzipain as a possible target protein, suggesting that (R)-salsolinol can be used as a prototype for drug design studies in Chagas disease.

Background: Importance of microbial metabolites in food, detergent, pharmaceutical, nutraceutical and cosmetic industries has now been widely established. To fulfill the requirement of these industries, psychrophilic/psychrotrophic marine microbes are being explored. These microbes help in the production of metabolites that are active and stable at extreme physiological conditions. In correlation with this scenario, the present study reports identification of 14 bacterial isolates (BRI 32- BRI 45) from marine water samples (out of which 4 are Antarctic) with emphasis on their biotechnologically important characters. Material and Methods: Bacterial isolates were identified using 16S rRNA gene sequencing. Growth of the isolates under different physiological conditions of temperature (10°C to 45°C), pH (3-10) and concentration of NaCI (0-20%) was studied. Further, the isolates were examined for their ability to produce i) polyunsaturated fatty acids, ii) industrially important enzymes and their potential to produce bio-surfactant. Results: 16S rRNA gene sequence analysis revealed that the isolates belonged to Halomonas, Brevibacillus, Kocuria and Oceanobacillus genera. Our results indicated that the isolates could grow over a wide range of physiological conditions of pH (3-10), temperature (10-45°C) and NaCI concentration. Eight out of 14 isolates showed the presence of omega-3 and omega-6 fatty acids. BRI 34 was found to produce significant amounts of eicosapentaenoic acid (39.66%). Most of the isolates exhibited the ability to produce 3 or 4 enzymes. Only BRI 35 showed potential for biosurfactant production. Conclusions: Our findings suggest potential of these isolates for biotechnological applications.