Marine Peptides and Their Anti-Infective Activities

Marine bioresources are a valuable source of bioactive compounds with industrial and nutraceutical potential. Numerous clinical trials evaluating novel chemotherapeutic agents derived from marine sources have revealed novel mechanisms of action. Recently, marine-derived bioactive peptides have attracted attention owing to their numerous beneficial effects. Moreover, several studies have reported that marine peptides exhibit various anti-infective activities, such as antimicrobial, antifungal, antimalarial, antiprotozoal, anti-tuberculosis, and antiviral activities. In the last several decades, studies of marine plants, animals, and microbes have revealed tremendous number of structurally diverse and bioactive secondary metabolites. However, the treatments available for many infectious diseases caused by bacteria, fungi, and viruses are limited. Thus, the identification of novel antimicrobial peptides should be continued, and all possible strategies should be explored. In this review, we will present the structures and anti-infective activity of peptides isolated from marine sources (sponges, algae, bacteria, fungi and fish) from 2006 to the present.     

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

Oceans are a rich source of structurally unique bioactive compounds from the perspective of potential therapeutic agents. Marine peptides are a particularly interesting group of secondary metabolites because of their chemistry and wide range of biological activities. Among them, cyclic peptides exhibit a broad spectrum of antimicrobial activities, including against bacteria, protozoa, fungi, and viruses. Moreover, there are several examples of marine cyclic peptides revealing interesting antimicrobial activities against numerous drug-resistant bacteria and fungi, making these compounds a very promising resource in the search for novel antimicrobial agents to revert multidrug-resistance. This review summarizes 174 marine cyclic peptides with antibacterial, antifungal, antiparasitic, or antiviral properties. These natural products were categorized according to their sources—sponges, mollusks, crustaceans, crabs, marine bacteria, and fungi—and chemical structure—cyclic peptides and depsipeptides. The antimicrobial activities, including against drug-resistant microorganisms, unusual structural characteristics, and hits more advanced in (pre)clinical studies, are highlighted. Nocathiacins I–III (91–93), unnarmicins A (114) and C (115), sclerotides A (160) and B (161), and plitidepsin (174) can be highlighted considering not only their high antimicrobial potency in vitro, but also for their promising in vivo results. Marine cyclic peptides are also interesting models for molecular modifications and/or total synthesis to obtain more potent compounds, with improved properties and in higher quantity. Solid-phase Fmoc- and Boc-protection chemistry is the major synthetic strategy to obtain marine cyclic peptides with antimicrobial properties, and key examples are presented guiding microbiologist and medicinal chemists to the discovery of new antimicrobial drug candidates from marine sources.     

A Comprehensive Update on the Bioactive Compounds from Seagrasses

Marine angiosperms produce a wide variety of secondary metabolites with unique structural features that have the potential to be developed as effective and potent drugs for various diseases. Recently, research trends in secondary metabolites have led to drug discovery with an emphasis on their pharmacological activity. Among marine angiosperms, seagrasses have been utilized for a variety of remedial purposes, such as treating fevers, mental disorders, wounds, skin diseases, muscle pain, and stomach problems. Hence, it is essential to study their bioactive metabolites, medical properties, and underlying mechanisms when considering their pharmacological activity. However, there is a scarcity of studies on the compilation of existing work on their pharmacological uses, pharmacological pathways, and bioactive compounds. This review aims to compile the pharmacological activities of numerous seagrass species, their secondary metabolites, pharmacological properties, and mechanism of action. In conclusion, this review highlights the potency of seagrasses as a promising source of natural therapeutical products for preventing or inhibiting human diseases.     

Natural Products from Marine Fungi—Still an Underrepresented Resource

Marine fungi represent a huge potential for new natural products and an increased number of new metabolites have become known over the past years, while much of the hidden potential still needs to be uncovered. Representative examples of biodiversity studies of marine fungi and of natural products from a diverse selection of marine fungi from the author’s lab are highlighting important aspects of this research. If one considers the huge phylogenetic diversity of marine fungi and their almost ubiquitous distribution, and realizes that most of the published work on secondary metabolites of marine fungi has focused on just a few genera, strictly speaking Penicillium, Aspergillus and maybe also Fusarium and Cladosporium, the diversity of marine fungi is not adequately represented in investigations on their secondary metabolites and the less studied species deserve special attention. In addition to results on recently discovered new secondary metabolites of Penicillium species, the diversity of fungi in selected marine habitats is highlighted and examples of groups of secondary metabolites produced by representatives of a variety of different genera and their bioactivities are presented. Special focus is given to the production of groups of derivatives of metabolites by the fungi and to significant differences in biological activities due to small structural changes.     

Metabolites of Marine Sediment-Derived Fungi: Actual Trends of Biological Activity Studies

Marine sediments are characterized by intense degradation of sedimenting organic matter in the water column and near surface sediments, combined with characteristically low temperatures and elevated pressures. Fungi are less represented in the microbial communities of sediments than bacteria and archaea and their relationships are competitive. This results in wide variety of secondary metabolites produced by marine sediment-derived fungi both for environmental adaptation and for interspecies interactions. Earlier marine fungal metabolites were investigated mainly for their antibacterial and antifungal activities, but now also as anticancer and cytoprotective drug candidates. This review aims to describe low-molecular-weight secondary metabolites of marine sediment-derived fungi in the context of their biological activity and covers research articles published between January 2016 and November 2020.     

Recent Discoveries on Marine Organism Immunomodulatory Activities

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

Immense essence of excellence: marine microbial bioactive compounds

Oceans have borne most of the biological activities on our planet. A number of biologically active compounds with varying degrees of action, such as anti-tumor, anti-cancer, anti-microtubule, anti-proliferative, cytotoxic, photo protective, as well as antibiotic and antifouling properties, have been isolated to date from marine sources. The marine environment also represents a largely unexplored source for isolation of new microbes (bacteria, fungi, actinomycetes, microalgae-cyanobacteria and diatoms) that are potent producers of bioactive secondary metabolites. Extensive research has been done to unveil the bioactive potential of marine microbes (free living and symbiotic) and the results are amazingly diverse and productive. Some of these bioactive secondary metabolites of microbial origin with strong antibacterial and antifungal activities are being intensely used as antibiotics and may be effective against infectious diseases such as HIV, conditions of multiple bacterial infections (penicillin, cephalosporines, streptomycin, and vancomycin) or neuropsychiatric sequelae. Research is also being conducted on the general aspects of biophysical and biochemical properties, chemical structures and biotechnological applications of the bioactive substances derived from marine microorganisms, and their potential use as cosmeceuticals and nutraceuticals. This review is an attempt to consolidate the latest studies and critical research in this field, and to showcase the immense competence of marine microbial flora as bioactive metabolite producers. In addition, the present review addresses some effective and novel approaches of procuring marine microbial compounds utilizing the latest screening strategies of drug discovery.     

Marine-Derived Indole Alkaloids and Their Biological and Pharmacological Activities

Novel secondary metabolites from marine macroorganisms and marine-derived microorganisms have been intensively investigated in the last few decades. Several classes of compounds, especially indole alkaloids, have been a target for evaluating biological and pharmacological activities. As one of the most promising classes of compounds, indole alkaloids possess not only intriguing structural features but also a wide range of biological/pharmacological activities including antimicrobial, anti-inflammatory, anticancer, antidiabetic, and antiparasitic activities. This review reports the indole alkaloids isolated during the period of 2016–2021 and their relevant biological/pharmacological activities. The marine-derived indole alkaloids reported from 2016 to 2021 were collected from various scientific databases. A total of 186 indole alkaloids from various marine organisms including fungi, bacteria, sponges, bryozoans, mangroves, and algae, are described. Despite the described bioactivities, further evaluation including their mechanisms of action and biological targets is needed to determine which of these indole alkaloids are worth studying to obtain lead compounds for the development of new drugs.     

Marine carotenoids and cardiovascular risk markers

Marine carotenoids are important bioactive compounds with physiological activities related to prevention of degenerative diseases found principally in plants, with potential antioxidant biological properties deriving from their chemical structure and interaction with biological membranes. They are substances with very special and remarkable properties that no other groups of substances possess and that form the basis of their many, varied functions and actions in all kinds of living organisms. The potential beneficial effects of marine carotenoids have been studied particularly in astaxanthin and fucoxanthin as they are the major marine carotenoids. Both these two carotenoids show strong antioxidant activity attributed to quenching singlet oxygen and scavenging free radicals. The potential role of these carotenoids as dietary anti-oxidants has been suggested to be one of the main mechanisms for their preventive effects against cancer and inflammatory diseases. The aim of this short review is to examine the published studies concerning the use of the two marine carotenoids, astaxanthin and fucoxanthin, in the prevention of cardiovascular diseases.     

Benefits under the Sea: The Role of Marine Compounds in Neurodegenerative Disorders

Marine habitats offer a rich reservoir of new bioactive compounds with great pharmaceutical potential; the variety of these molecules is unique, and its production is favored by the chemical and physical conditions of the sea. It is known that marine organisms can synthesize bioactive molecules to survive from atypical environmental conditions, such as oxidative stress, photodynamic damage, and extreme temperature. Recent evidence proposed a beneficial role of these compounds for human health. In particular, xanthines, bryostatin, and 11-dehydrosinulariolide displayed encouraging neuroprotective effects in neurodegenerative disorders. This review will focus on the most promising marine drugs’ neuroprotective potential for neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. We will describe these marine compounds’ potential as adjuvant therapies for neurodegenerative diseases, based on their antioxidant, anti-inflammatory, and anti-apoptotic properties.     

Production of bioactive secondary metabolites by marine vibrionaceae

Bacteria belonging to the Vibrionaceae family are widespread in the marine environment. Today, 128 species of vibrios are known. Several of them are infamous for their pathogenicity or symbiotic relationships. Despite their ability to interact with eukaryotes, the vibrios are greatly underexplored for their ability to produce bioactive secondary metabolites and studies have been limited to only a few species. Most of the compounds isolated from vibrios so far are non-ribosomal peptides or hybrids thereof, with examples of N-containing compounds produced independent of nonribosomal peptide synthetases (NRPS). Though covering a limited chemical space, vibrios produce compounds with attractive biological activities, including antibacterial, anticancer, and antivirulence activities. This review highlights some of the most interesting structures from this group of bacteria. Many compounds found in vibrios have also been isolated from other distantly related bacteria. This cosmopolitan occurrence of metabolites indicates a high incidence of horizontal gene transfer, which raises interesting questions concerning the ecological function of some of these molecules. This account underlines the pending potential for exploring new bacterial sources of bioactive compounds and the challenges related to their investigation.     

Sponges and Their Symbionts as a Source of Valuable Compounds in Cosmeceutical Field

In the last decades, the marine environment was discovered as a huge reservoir of novel bioactive compounds, useful for medicinal treatments improving human health and well-being. Among several marine organisms exhibiting biotechnological potential, sponges were highlighted as one of the most interesting phyla according to a wide literature describing new molecules every year. Not surprisingly, the first marine drugs approved for medical purposes were isolated from a marine sponge and are now used as anti-cancer and anti-viral agents. In most cases, experimental evidence reported that very often associated and/or symbiotic communities produced these bioactive compounds for a mutual benefit. Nowadays, beauty treatments are formulated taking advantage of the beneficial properties exerted by marine novel compounds. In fact, several biological activities suitable for cosmetic treatments were recorded, such as anti-oxidant, anti-aging, skin whitening, and emulsifying activities, among others. Here, we collected and discussed several scientific contributions reporting the cosmeceutical potential of marine sponge symbionts, which were exclusively represented by fungi and bacteria. Bioactive compounds specifically indicated as products of the sponge metabolism were also included. However, the origin of sponge metabolites is dubious, and the role of the associated biota cannot be excluded, considering that the isolation of symbionts represents a hard challenge due to their uncultivable features.     

Marine Carotenoids against Oxidative Stress: Effects on Human Health

Carotenoids are lipid-soluble pigments that are produced in some plants, algae, fungi, and bacterial species, which accounts for their orange and yellow hues. Carotenoids are powerful antioxidants thanks to their ability to quench singlet oxygen, to be oxidized, to be isomerized, and to scavenge free radicals, which plays a crucial role in the etiology of several diseases. Unusual marine environments are associated with a great chemical diversity, resulting in novel bioactive molecules. Thus, marine organisms may represent an important source of novel biologically active substances for the development of therapeutics. In this respect, various novel marine carotenoids have recently been isolated from marine organisms and displayed several utilizations as nutraceuticals and pharmaceuticals. Marine carotenoids (astaxanthin, fucoxanthin, β-carotene, lutein but also the rare siphonaxanthin, sioxanthin, and myxol) have recently shown antioxidant properties in reducing oxidative stress markers. This review aims to describe the role of marine carotenoids against oxidative stress and their potential applications in preventing and treating inflammatory diseases.     

Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications

Cyanobacteria are photosynthetic prokaryotic organisms which represent a significant source of novel, bioactive, secondary metabolites, and they are also considered an abundant source of bioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin, cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results in successful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied to medical research have demonstrated an exciting future with great potential to be developed into new medicines. Most of these compounds have exhibited strong pharmacological activities, including neurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so these metabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existing issues associated with chemical isolation, including small yields, and may be necessary to better investigate their biological activities. Herein, we highlight the total synthesized and stereochemical determinations of the cyanobacterial bioactive compounds. Furthermore, this review primarily focuses on the biotechnological applications of cyanobacteria, including applications as cosmetics, food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compounds in potential medicinal applications for various human diseases are discussed.     

A Soft Spot for Chemistry–Current Taxonomic and Evolutionary Implications of Sponge Secondary Metabolite Distribution

Marine sponges are the most prolific marine sources for discovery of novel bioactive compounds. Sponge secondary metabolites are sought-after for their potential in pharmaceutical applications, and in the past, they were also used as taxonomic markers alongside the difficult and homoplasy-prone sponge morphology for species delineation (chemotaxonomy). The understanding of phylogenetic distribution and distinctiveness of metabolites to sponge lineages is pivotal to reveal pathways and evolution of compound production in sponges. This benefits the discovery rate and yield of bioprospecting for novel marine natural products by identifying lineages with high potential of being new sources of valuable sponge compounds. In this review, we summarize the current biochemical data on sponges and compare the metabolite distribution against a sponge phylogeny. We assess compound specificity to lineages, potential convergences, and suitability as diagnostic phylogenetic markers. Our study finds compound distribution corroborating current (molecular) phylogenetic hypotheses, which include yet unaccepted polyphyly of several demosponge orders and families. Likewise, several compounds and compound groups display a high degree of lineage specificity, which suggests homologous biosynthetic pathways among their taxa, which identifies yet unstudied species of this lineage as promising bioprospecting targets.     

Marine Anticancer Agents: An Overview with a Particular Focus on Their Chemical Classes

The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.     

Anti-Larval and Anti-Algal Natural Products from Marine Microorganisms as Sources of Anti-Biofilm Agents

Bacteria growing inside biofilms are more resistant to hostile environments, conventional antibiotics, and mechanical stresses than their planktonic counterparts. It is estimated that more than 80% of microbial infections in human patients are biofilm-based, and biofouling induced by the biofilms of some bacteria causes serious ecological and economic problems throughout the world. Therefore, exploring highly effective anti-biofilm compounds has become an urgent demand for the medical and marine industries. Marine microorganisms, a well-documented and prolific source of natural products, provide an array of structurally distinct secondary metabolites with diverse biological activities. However, up to date, only a handful of anti-biofilm natural products derived from marine microorganisms have been reported. Meanwhile, it is worth noting that some promising antifouling (AF) compounds from marine microbes, particularly those that inhibit settlement of fouling invertebrate larvae and algal spores, can be considered as potential anti-biofilm agents owing to the well-known knowledge of the correlations between biofilm formation and the biofouling process of fouling organisms. In this review, a total of 112 anti-biofilm, anti-larval, and anti-algal natural products from marine microbes and 26 of their synthetic analogues are highlighted from 2000 to 2021. These compounds are introduced based on their microbial origins, and then categorized into the following different structural groups: fatty acids, butenolides, terpenoids, steroids, phenols, phenyl ethers, polyketides, alkaloids, flavonoids, amines, nucleosides, and peptides. The preliminary structure-activity relationships (SAR) of some important compounds are also briefly discussed. Finally, current challenges and future research perspectives are proposed based on opinions from many previous reviews.     

Marine bioactives as functional food ingredients: potential to reduce the incidence of chronic diseases

The marine environment represents a relatively untapped source of functional ingredients that can be applied to various aspects of food processing, storage, and fortification. Moreover, numerous marine-based compounds have been identified as having diverse biological activities, with some reported to interfere with the pathogenesis of diseases. Bioactive peptides isolated from fish protein hydrolysates as well as algal fucans, galactans and alginates have been shown to possess anticoagulant, anticancer and hypocholesterolemic activities. Additionally, fish oils and marine bacteria are excellent sources of omega-3 fatty acids, while crustaceans and seaweeds contain powerful antioxidants such as carotenoids and phenolic compounds. On the basis of their bioactive properties, this review focuses on the potential use of marine-derived compounds as functional food ingredients for health maintenance and the prevention of chronic diseases.