EJBR2021v11i1art122-133 ISSN 2449-8955 European Journal of Biological Research Review Article European Journal of Biological Research 2021; 11(1): 122-133 DOI: http://dx.doi.org/10.5281/zenodo.4384158 Marine biomolecules: a promising approach in therapy and biotechnology Asmaa Chbel1, Aurelio Serrano Delgado2, Abdelaziz Soukri1, Bouchra El Khalfi1* 1 Laboratory of Physiopathology, Molecular Genetics & Biotechnology, Faculty of Sciences Ain Chock, Research Center of Health & Biotechnology, Hassan II University of Casablanca, 20100 Casablanca, Morocco 2 Institute for Plant Biochemistry and Photosynthesis (IBVF), CSIC-Universidad de Sevilla, 41092 Seville, Spain * Corresponding author: bouchra.elkhalfi@gmail.com Received: 20 October 2020; Revised submission: 04 December 2020; Accepted: 22 December 2020 http://www.journals.tmkarpinski.com/index.php/ejbr Copyright: © The Author(s) 2021. Licensee Joanna Bródka, Poland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) ABSTRACT: The marine environment is characterized by a wide diversity of microorganisms among which marine bacteria. To insure their survival in hostile conditions where they face high competition with pathogenic microorganisms, they produce various kinds of bioactive molecules within biofilms with unique structural and functional features. As example: marine peptides which provide a broad spectrum of antimicrobial, antitumoral, antiviral and anti-inflammatory activities, in addition to marine exopolysaccharides showing antifouling and antifungal activities, immunomodulatory properties, emulsion stabilization capacity with other various potentials. Some biofilms have shown a beneficial role for aquaculture, among which enhancement of growth performance and improvement of water quality, while others are threatening not only aquaculture and maritime fields, but also medicine and food industry. Thus, marine bioactive compounds are promising preventing agents for the establishment and growth of fouling microorganisms, which may be useful in different fields in order to decrease economic losses and avoid foodborne illnesses. Keywords: Marine biomolecules; Biofilms; Health issues; Aquaculture. 1. INTRODUCTION The marine environment hosts an immense biological, chemical and ecological diversity [1]. It is characterized by hostile environmental conditions in terms of variation of salinity, temperature and pressure [2] which have favored production of a great variety of novel bioactive molecules with unique structural and functional features. These polymeric substances are of renewed interest to many sectors of industrial human activities including food industries, pharmaceuticals and drug delivery due to their diverse biological and chemical properties such as antitumor, immunostimulatory, anti-inflammatory, antibacterial, antifouling and antioxidant activities [3]. Many naturally bioactive compounds are secreted on biological or non-biological surfaces submerged in the marine environment as living tissues, aquatic equipments and water distribution systems which may be covered with densely colonized sessile communities known as biofilms, enclosing microbial cells [2, 4]. The main advantage of biofilm formation is the protection of microorganisms from attack by bacterial and viral pathogens which extend their survival periods in extreme marine environments [5]. Additionally, it has been used as an ecofriendly strategy whereby substrate based aquaculture using biofilms has contributed to improvement of water quality resulting in Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 123 European Journal of Biological Research 2021; 11(1): 122-133 enhanced growth of marine organisms of interest (fishes, shellfishes, and aquatic plants). Nevertheless, these sessile biological assemblies may turn virulent and cause health diseases since they may develop on seafood. They also lead to significant economic losses in the maritime field due to biofouling and materials biocorrosion [6]. In this review, we give a general overview on the main classes of bioactive molecules produced by marine bacteria and their diverse biological activities which provide promising applications in various fields. We also describe their living modes which may have advantages and inconveniences for many aquatic organisms and eventually to human health as well as to the whole marine ecosystem. 2. MARINE DIVERSITY Oceans are colonized by microbial species that are essential for marine ecosystems and have pivotal roles in global biogeochemical cycles. The marine environment is characterized by a taxonomic richness where bacteria are very abundant. A recent metagenomics study has reported the partition of bacterial genera communities to geographic locations. Cyanobacteria, Alphaproteobacteria and Flavobacteria dominate the photic zone samples while the aphotic zone is colonized mainly by Alphaproteobacteria, Deferribacteres, Deltaproteobacteria and Gammaproteobacteria [7]. A significant part of the world ocean is characterized by harsh conditions in terms of low nutrients, low concentrations of biodegradable organic carbon, variation of temperature, pressure and salinity. Thus, microorganisms are classified into halotolerant: which do not require salt for growth but tolerate it, then can grow in moderately salty environments, and halophilic: for which the presence of salt is essential for their survival and growth, then they only thrive in highly saline environments [8]. In parallel, microorganisms are adapted to osmotic stress. They have an endogenous balance of pressure and resistance to osmotic stress apart from any external osmoprotection. Therefore, they carry the genetic information and the enzymatic machinery necessary for osmotolerance which allow them to maintain an internal osmotic pressure higher than the surrounding environment [9]. Hence, bacterial adaptations represent a driving force leading to new secondary metabolic products that function as a defense strategy against natural predators in order to insure their survival [5]. In this regard, the most reported genera from which novel metabolites have been isolated are phylogenetically diverse, including among them Pseudomonas, Alteromonas, Vibrio, Bacillus, Streptomyces. For example the widespread genus Pseudomonas, is a group of gram negative and easily cultivable gamma-proteobacteria that includes numerous marine species of great importance due to their production of various useful compounds such as antibiotics, enzymes, antitoxins, antitumorals and antivirals [2]. Moreover, widespread marine actinomycetes are known by their production of a great variety of bioactive compounds as was reported with Pseudonocardia sp. HS7, Nocardiopsis sp. strain HYJ128, Marinispora strain CNQ-140, Streptomyces sp. CNQ343 and many other species [10] as shown in Table 1. On the other hand, Vibrio is an example of bacterial genus which belongs to microbial pathogens of clinical importance for humans and many marine animals. It contains different species many of which of marine and other aquatic environments, but V. alginolyticus, V. vulnificus, V. parahaemolyticus, V. cholerae, V. fluvialis and V. mimicus are the most dangerous reported species to humans and other animals. They have been associated with infections in case of wounds or after exposure to polluted water, or after eating contaminated food [11]. Thus many researchers have discovered natural compounds isolated from sponge bacterial symbionts inhibiting virulent Vibrio species such as docosane acting against V. harveyi, V. parahaemolyticus and V. vulnificus [5]. In addition, marine fungi are sources of structurally unique products. Many of marine fungal metabolites have been classified as potential therapeutic agents owned to their antimicrobial, anticancer, antiviral and antimarine fungal-inflammatory activities [10, 12] as shown in Table 1. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 124 European Journal of Biological Research 2021; 11(1): 122-133 Table 1. Potential therapeutic bioactive molecules produced by marine bacteria and fungi. Marine microorganisms Source Biomolecules Activity References Bacteria Pseudoalteromonas piscicida 3,4- dibromopyrrole- 2,5-dione Antibacterial [10] Pseudomonas sp. Pyolipic acid and phenazine-1-carboxylic acid Antifouling [10] Vibrio sp. WMBA Aqabamycins A−D Antibacterial [10] Bacillus subtilis strain 109GGC020 Gageotetrins A−C Antimicrobial [10] Bacillus amyloliquefaciens SCSIO 00856 Macrolactin V Antibacterial [10] Bacillus sp. 09ID194 Macrolactins X−Z Antibacterial [10] Bacillus licheniformis ATCC 14580 BL00275 Antibiofilm [10] Lyngbya majuscula Dolastatin Antilarval settlement [10] Streptomyces caelestis Citreamicin θ A-B-C Antibacterial [10] Streptomyces roseogilvus Griseoviridin Antibacterial [10] Streptomyces fradiae strain PTZ0025 Fradimycins A-B Antibacterial [10] Kocuria palustris Kocurin Antibacterial [10] Pseudonocardia sp. Diazaanthraquinone Antibacterial [10] Streptosporangium strain DSZM 4594 Iodinin Antibacterial [10] Streptomyces sp. SCSIO 10355 Strepsesquitriol Anti-inflammatory [12] Streptomyces strain M491 T-Muurolol sesquiterpenes Cytotoxic [12] Micromonospora sp. strain WMMC-218 Micromonohalimane B Antibacterial [12] Verrucosispora gifhornensis YM28-088 Gifhornenolones Cytotoxic [12] Actinomycetes isolate CNH-099 Neomarinones Cytotoxic [12] Erythrobacter sp. strain SNB-035 Erythrazole Cytotoxic [12] Fungi Penicillium sp. SCS-KFD09 Chrodrimanins Antiviral [12] Alternaria alternate strain (k21-1) Sesteralterin Antialgal/ Antibacterial [12] Strain 95-1005C Chondrostereum sp. SF002 Hirsutanol A Antitumoral [12] Aspergillus sp. CNL-523 Cryptosphaerolide Cytotoxic [12] Curvularia sp. strain M12 Curvularin and (S)-dehydrocurvularin Antifungal [10] Penicillium thomii KMM 4667 Thomimarine E Anti-inflammatory [12] Penicillium sp. Ligerin Antiproliferative [12] Xylariaceae sp. Eremophilane-type sesquiterpenoids Cytotoxic [12] Eupenicillium sp. Curvularin and (S)-dehydrocurvularin Antiviral [10] Paraphaeosphaeria strain N-119 Curvularin and αβ-dehydrocurvularin Antifungal/ Anti-inflammatory [10] Phomopsis sp. hzla01-1 Modiolides A and B Antibacterial/ Antifungal [10] Penicillium cf. montanense Phomolide A and B Antibacterial/ Antifungal [10] Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 125 European Journal of Biological Research 2021; 11(1): 122-133 Marine microorganisms Source Biomolecules Activity References Cladosporium spp. Xestodecalactones A–C Dendrodolides A, C, M Antifungal/ Antibacterial [10] Streptomyces sp. strain 12A35 Lobophorins H and I Antibacterial [10] Penicillium sp. β-resorcylicacid lactones Antifungal [10] Aspergillus sp. Didehydrosydonic acid Cytotoxic [12] Aspergillus sp. Disydonols Cytotoxic [12] Periconia byssoides Pers. Peribysins Cell-adhesion inhibitors [12] Aspergillus versicolor Insulicolide A Cytotoxic [12] Penicillium sp. Breviones Antiviral/ Cytotoxic [12] Table 2. Potential therapeutic bioactive molecules produced by seaweeds and sponges. Marine organisms Source Biomolecules Activity References Seaweeds Callophycus serratus 5- and 16-membered bromophycolides J-Q Antibacterial [16] Neurymenia fraxinifolia Neurymenolides A and B Antibacterial [16] Ecklonia kurome 8′-bieckol, eckol, dieckol, phloroglucinol & phlorofucofuroeckol-A Bactericidal [16] Ecklonia cava Dieckol Fungicidal [16] Ecklonia cava Eckol Antimicrobial [16] Ishige foliacea Octaphlorethol A Anti-inflammatory [16] Eisenia arborea Phlorofucofuroeckol B Anti-inflammatory [16] Vidalia obtusaloba Vidalols A and B Anti-inflammatory [16] Porphyra dentate Catechol & rutin Anti-inflammatory/ Antioxidant [16] Eisenia bicyclis Fucosterol Antidepressant [16] Sargassum fusiforme Saringosterol3,6,17-trihydroxy Antidepressant [17] Turbinaria conoides Stigmasta-4,7,24(28)-triene Antifungal [17] Sargassum horneri β-sitosterol Antidepressant [17] Ecklonia stolonifera 24-hydroperoxy24- vinylcholesterol Anti-cholinesterase [17] Ecklonia bicyclis Phloroglucinol, eckol, phlorofucofuroeckol A & dioxinodehydroeckol Anti-inflammatory [17] Sponges Phycopsis sp. Dichloromethane Antibacterial [18] Agelas dispar Methanol bromopyrrole alkaloids Antibacterial [18] Latrunculia sp. and Negombata sp. Discorhabdin R Antibacterial [18] Petrosia sp. Methanol soluble extract Cytotoxicity [18] Cymbastela sp. Aglestatin A Cytotoxicity [18] Pachastrella sp. and Jaspis sp. Pectenotoxin II and Psammaplin A Antitumoral [18] Cymbastela sp. Methylicosadienoicacids Larvicidal [18] Hyrtios sp. Puupehenone Antiviral/Antifungal [18] Fasciospongia covernosa Cacospongionolide B Antimicrobial [18] Polyfibrospongia sp. Hennoxazoles A-D Antiviral [19] Polyfibrospongia sp. Miyakolide Antitumoral [19] Axinella sp./ Halichondrida Axinellamines B–D Antibacterial [19] Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 126 European Journal of Biological Research 2021; 11(1): 122-133 Marine organisms Source Biomolecules Activity References Cribrochalina sp. Cribrostatin 6 Antibacterial [19] Aaaptos aaptos Isoaaptamine Antibacterial [19] Arenosclera brasiliensis Arenosclerins A–C Antibacterial [19] Arenosclera brasiliensis Haliclona cyclamine E Antibacterial [19] Caminus sphaeroconia Caminosides A–D Antibacterial [19] Jaspis sp. Jaspamide Antiviral [19] Hymeniacidon sp. Monamphilectine A Antimalarial [19] Moreover, the marine environment contains diverse marine multicellular macroscopic organisms including seaweeds and invertebrates which represent other potential resources of natural products. Seaweeds (also called macroalgae) are an heterogeneous group of macroscopic, multicellular, marine macroalgal species; they can be divided into three main phyla: red (Rhodophyceae), brown (Phaeophyceae), and green (Chlorophyceae) macroalgae. They comprise a highly significant element of the marine ecosystem contributing a major feeding ground for marine lives as well as potentially therapeutic resources for human. Numerous secondary bioactive metabolites including carotenoids, polyphenolics, polysaccharides, and sterols have been isolated from seaweed and applied in different industrial usages due to their health promoting therapeutic qualities combatting various human ailments, comprising antihypertensive, antioxidant, antithrombotic and immunomodulatory properties [13]. On the other hand, invertebrates comprise a wide range of animal species belonging to various phyla with different morphological structures and physiology, including Mollusca, Arthropoda, Porifera and Echinodermata, from which secondary metabolites mainly alkaloids, terpenoids and steroids, have shown biological activities and are commercially applied [14]. Additionally, marine invertebrates have been reported to actively interact with their associated bacterial symbionts resulting in the discovery of new compounds as biosurfactants and exopolysaccharides, with application in pharmaceutical and medical fields for their antifungal, antiprotozoal, antiviral and antifouling functions [15]. The exploration of the different phyla is related to the discovery of a greater amount of natural substances with functional biodiversity as shown in Table 2. 3. MARINE BIOMOLECULES WITH RELEVANT CHEMICAL AND THERAPEUTIC PROPERTIES 3.1. Chitin and chitosan Chitin and chitosan are natural glucosamine biopolymers mostly found in the structural backbone exoskeleton of marine invertebrates. Chitin is a neutral crystalline substance with a structure of n-acetyl- glucosamine monomerswidely derived from shrimps, crabs and squid which revealed an important role in maintaining cutaneous homeostasis and neutralizing free radicals activity [20]. Its deacetylated derivative called chitosan is found in lobster, crab, shrimp and also in mollusks exoskeletons. It is recognized by its multiple applications in cosmeceutical formulations for skin care, as moisturizer because of its water absorbing properties. Its oligomers revealed an important role in stimulating fibroblast production, providing wound healing benefits, and exhibiting antioxidant and metalloproteinase inhibiting effects. It has also antimicrobial activity against bacteria, yeasts and fungi. In the form of nanoparticles, chitosan helps to protect from aggressive environmental factors such as light and oxidation [20]. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 127 European Journal of Biological Research 2021; 11(1): 122-133 Additionally, marine bacterial chitinases are exoenzymes that play an important role in the nutrient cycling and waste management in the oceans. They convert chitin to biologically useful carbon and nitrogen forms for marine organisms and biodegrade exoskeletal chitinous wastes generated from the production and processing of shellfish to reduce environmental pitfalls [21]. 3.2. Carotenoids Carotenoids, or tetraterpenoids, are important yellow, red, and orange coloured pigments isolated from photosynthetic bacteria, algae and plants that have relevant antioxidant roles. Physiologically, oxidative stress is implicated in pathological degenerative processes and aging, atherosclerosis, cancer, malaria, neurodegenerative diseases and arthritis. Thus, carotenoids have proven their ability to prevent, delay, or neutralize the effects of oxidative stress and suppression and/or scavenging of free radicals. Beta carotene and lycopene have been reported to remediate ultraviolet oxidative damage to the skin and retina [22]. In addition, lutein and zeaxanthin have shown a protecting role against age-related macular degeneration through antioxidant and light protective mechanisms [23]. Zeaxanthin, has also shown to have various beneficial effects for human health due to its ability to quench free radicals, exert antioxidant effects, as well as decrease inflammation [24]. Astaxanthin, another carotenoid has gained a growing interest as a multi-target pharmacological agent against neurological diseases such as Alzheimer’s disease, Parkinson’s disease, neuropathic pain, aging, depression, and autism. It has shown a neuroprotective effects due to its anti-inflammatory, antioxidative, and anti-apoptotic properties to tackle neurodegeneration [25, 26]. Moreover, several biological properties are provided by fucoxanthin, a marine natural compound produced by brown algae and diatoms, reported to provide anti-obesity, anti-diabetic, anticancer, antioxidant and antimicrobial activities [27]. 3.3. Polysaccharides Polysaccharides are the high molecular weight carbohydrate molecules, mostly polymers of glucose, linked through glycosidic bonds. They have known a grown interest in various industries which demand applications of natural polymers for their diverse biological activities. For example, a sulfated O- polysaccharide isolated from the marine bacterium Poseidonocella sedimentorum KMM 9023T has shown high anticancer activity. It inhibits colony formation of human colorectal adenocarcinoma HT-29, human breast adenocarcinoma MCF-7 and human malignant melanoma SK-MEL-5 cells [28]. Anticancer therapeutic properties have also been shown for other carbohydrate types, as is the case of the sulfated lipopolysaccharide isolated from the marine bacterium Cobetia litoralis KMM 3880 3880T. It inhibits colony formation of human melanoma SK-MEL-28 and colorectal carcinoma HTC-116 cells [29]. Additionally, these natural polymers are used in cosmetics in order to prevent aging, inflammation, and skin degradation as they are formulated with ingredients including vitamins, minerals and antioxidants [30]. They are also commercialized as emulsifiers, gelling agents, viscosifiers, stabilizers, and texture enhancers provided by fucoidans isolated from brown algae, carrageenans from red algae, and alginate and agar from brown and red algae [31]. 3.4. Peptides Recently, many biologically active compounds of peptidic nature have proven their ability to impair biofilms development. They may represent a biofilm preventing strategy for investigation in aquaculture, maritime fields and food industries in order to reduce economical losses worldwide [32]. For example, a peptide molecule produced by Pseudoalteromonas sp. strain 3J6 called alterocin Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 128 European Journal of Biological Research 2021; 11(1): 122-133 impaired the ability of initial attachment of Paracoccus sp. strain 4M6, Vibrio sp. D01 and Vibrio tapetis to form biofilms. It has also impaired biofilm development by three human pathogenic strains: Pseudomonas aeruginosa, Salmonella enterica and Escherichia coli [33]. In the same way, another Pseudoalteromonas strain, Pseudoalteromonas sp. strain 41, has impaired biofilm development ofmany marine bacterial strains including Pseudoalteromonas sp. strain 3J6, Paracoccus sp. strain 4M6, Alteromonas sp. 1J3, Algibacter sp. 1M6, Micrococcus sp. 5J6 and Colwellia sp. 4J3 [34]. In addition, many microbes associated with marine living surfaces have been reported to secrete peptides with antifouling activity which inhibits the adhesion of biofilm bacteria and microalgae and showed inhibitory activities against larval forms of barnacle, polychaete, ascidian and spores of macroalgae [35]. 3.5. Antibiotics Marine microorganisms represent a significant source for the development of antibiotics. Most of them are synthesized by bacteria, in particular, actinomycetes which produce diverse products with clinical or pharmaceutical applications due to their broad spectrum of biological properties. For example, marthiapeptide A isolated from M. Thermotolerans SCSIO 00652, desotamide B isolated from Streptomyces scopuliridi SCSIO ZJ46, marfomycins A, B, and E isolated from Streptomyces drozdowiczii SCSIO 10141 and vitroprocines A-J derived from Vibrio sp. QWI-06 providing all of them antimicrobial activities. In addition, there are antibiotics with potent antitumor properties, they have been designated as spirotetronate polyketides, like lobophorin F isolated from Streptomyces SCSIO 01127, lobophorin H isolated from Streptomyces sp. 12A35S and abyssomicin C isolated from Verrucosispora strain AB 18-032 [36, 37]. On the other hand, marine fungi have been also considered as an excellent source of bioactive compounds since the discovery of the antibiotic cephalosporin. As example of natural compounds isolated from fungi, there are gliotoxin isolated from an Aspergillus sp., prenylxanthones and emerixanthones A–D isolated from Emericella sp. SCSIO 05240 and engyodontiumone H purified from Engyodontium album DFFSCS021 providing antifungal and antibacterial properties with many other antibiotics providing various biological activities [36]. 4. IMPACTS OF MARINE BIOFILMS 4.1. Advantages Bacterial biofilms are an extracellular matrix mainly composed of polysaccharides, proteins and lipids. It facilitates signals exchange and nutrient uptake between different bacterial species, and with other symbiotic microorganisms, like fungi and microalgae. This sessile form gives the bacterial community protection against a huge number of environmental stressors such as antimicrobial agents, predators, UV radiation, etc. [5, 38]. The nutritional composition of biofilms is considerably appropriate to fish dietary needs. Consequently, food availability as well as water quality improved by bacterial biofilms enhance aquaculture growth and production. It has been reported in a research that application of biofilm during the culture of fingerlings of the fish Catla catla has shown lower concentrations of total ammonia in comparison with control treatment [5]. Then, the presence in biofilms of nitrifying bacterial communities belonging to Nitrosomonas and Nitrosococcus genera helps in the management of water quality by decreasing ammonium level in cultured water with a parallel increase of nitrite and nitrate concentrations [6]. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 129 European Journal of Biological Research 2021; 11(1): 122-133 Aquaculture used to need water exchange for feed addition as well as preventing accumulation of toxic substances. However, frequent water exchange is expensive and may increase the risk of introducing bacterial pathogens and toxic metabolites, but since the use of biofilm has been introduced in aquaculture ponds, it is not required to exchange water [5, 6]. The use of biofilms sequesters excess nutrients such as dissolved phosphorus, ammonia ions and nitrates that are accumulated in aquaculture ponds including bacteria of the genera Nitrobacter, Nitrococcus, Nitrospira, and Nitrospin. It does not only maintain water quality but also reduce the occurrence of pathogenic microorganisms which may suppress microbial infection and prevent diseases. For example, Vibrio strain C33 a marine bacterium associated with the aquaculture of bivalve Agropecten purpuratus has been reported to produce bioactive compounds controlling the growth of pathogenic strains forming biofilms such as Vibrio alginolyticus, Vibrio anguillarum, Vibrio parahaemolyticus and Vibrio splendidus [39]. On the other hand, there are several situations in which higher organisms encourage biofilm formation by protective biofilms. One example of this feature is the macroalga Ulva lactuca, it encourages colonization by the marine gram negative bacterium, Pseudoalteromonas tunicate. This endophytic bacterium produces antifouling compounds identified as a large extracellular protein that inhibits colonization by other undesirable bacteria [40]. Thus, biofilm can be used as a novel alternative strategy of disease control in marine fisheries and aquaculture industries in order to improve growth performance and health conditions of aquatic organisms [41, 42]. It can also serve as active biofilters to absorb and degrade excessive nutrients and remove ammonia in seawater supply systems [43]. 4.2. Inconvenients Over the past few decades, the consumption of raw food including seafood products has grown as it has a high nutritional value. It contains proteins, omega-3 fatty acids, minerals and vitamins. Consequently, the occurrence of foodborne illnesses is increasing because of these new nutritional trends making food safety a universal issue [44]. Consumers are most vulnerable to foodborne illnesses because of dangerous bacterial pathogens found as biofilms on seafood formed by Listeria spp., Salmonella spp., Vibrio spp. (V. cholerae, V. parahaemolyticus, V. vulnificus), Clostridium spp. (C. perfringens, C. botulinum), Campylobacter spp., Shigella spp., etc. Other species of the genera Mycobacterium are also deleterious to humans health especially Mycobacterium marinum as well as a number of Streptococcus, Aeromonas, Erysipelothrix, and Pseudomonas species [45]. Some bacteria may produce potent natural toxins. Many of them are thermostable, and since they cannot be destroyed by food preparation methods (cooking, frying, freezing, etc.) they lead to acute illnesses such as emetic reaction, gastroenteric symptoms, and neurologic reactions [46]. When microorganisms form biofilm on food, they survive for long periods. Consequently, antibiotics and numerous chemical compounds habitually used in aquaculture to control the occurrence of these bacterial pathogens are less effective [47]. Moreover, these compounds have a negative impact not only on quality and safety of cultivated organisms (including oysters, mussels, fish and crustaceans) but also on human health, as well as on the environment [46]. Firstly, the excessive exposure may damage the nervous and immune systems and lead to cancer and impairment of reproductive development and function. Additionally, some seafood pathogens may become resistant to many drugs and the resistant determinants may be transmitted by horizontal gene transfer to bacterial human pathogens after consumption of contaminated seafood leading to dangerous outbreaks [47]. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 130 European Journal of Biological Research 2021; 11(1): 122-133 On the other hand, the marine environment is being progressively polluted by these wide varieties of drugs and chemicals. It is also affected by novel microbial communities colonization which may be developed on any submerged surface and cause biofouling and biocorrosion [48]. These ecological phenomena have major impacts on marine engineering contributing to economic losses worldwide. They can lead to reduction of heat transfer capacity of heat exchangers by 20 to 30% and decrease of underwater cameras and nephelometers effectiveness. They can also develop on ship hulls and boats which may increase their weight and consequently consumption of fuel, then increase CO2 emissions [49]. Thus, the discovery of novel secondary metabolites from the marine environment has been necessary to overcome biofilm issues occurring in marine habitats. An example of a non-toxic glycolipid biosurfactant named BS-SLSZ2 derived from a marine bacterium Staphylococcus lentus is used to treat aquaculture associated infections as it inhibits Vibrio harveyi and Pseudomonas aeruginosa biofilms. Vibrio harveyi biofilm is also inhibited by a lipopeptide of the fengycin family produced by the actinobacterium Nesterenkonia sp. MSA31, while another lipopeptide produced by a newly identified bacterium, Pontibacter korlensis strain SBK-47 named pontifactin exhibits an anti-adhesion potential against Vibrio cholerae. Therefore, marine secondary metabolites are taking a high interest for use as an eco-friendly manner in aquaculture ponds as they may act as biofilm controlling agents in order to decrease the usage of antibiotics in aquaculture settings [42, 50]. 5. CONCLUSION Marine species are taxonomically diverse, which makes them of a renewed interest for the discovery of a wide range of novel natural molecules. Marine secondary metabolites are recognized by unique structural and functional features. They provide diverse biological activities such as antitumor, immunostimulatory, anti- inflammatory, antibacterial, antifouling and antioxidant activities. Consequently, it makes them possess a great potential for exploitation in different areas such as pharmaceutical, cosmetics and food industries as well as maritime and aquaculture fields. Thus, the marine environment needs to be more explored to strengthen the use of natural bioactive compounds as an adequate alternative to synthetic molecules. Authors' Contributions: AC contributed in conception, design and writing. ASD and AS contributed in review and revision. BE contributed in conception, design and review. All authors read and approved the final manuscript. Conflict of Interest: The authors have no conflict of interest to declare. Acknowledgment: The acknowledgement goes to all authors for participating and facilitating the accomplishment of this study. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. REFERENCES 1. Romano G, Costantini M, Sansone C, Lauritano C, Ruocco N, Ianora A. Marine microorganisms as a promising and sustainable source of bioactive molecules. Mar Environ Res. 2017; 128: 58-69. 2. Jimeno J, Faircloth G, Sousa-Faro J, Scheuer P, Rinehart K. New marine derived anticancer therapeutics. A journey from the sea to clinical trials. Mar Drugs. 2004; 2: 14-29. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 131 European Journal of Biological Research 2021; 11(1): 122-133 3. Guezennec J. Deep-sea hydrothermal vents: A new source of innovative bacterial exopolysaccharides of biotechnological interest. J Ind Microbiol Biotechnol. 2002; 29: 204-208. 4. Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol. 2004; 2: 95-108. 5. Panday PK, Vivekanand B, Kundan K. Biofilm in aquaculture production. Afr J Microbiol Res. 2014; 8: 1434-1443. 6. Wahl M, Goecke F, Labes A, Dobretsov S, Weinberger F. The second skin: ecological role of epibiotic biofilms on marine organisms. Front Microbiol. 2012; 3: 1-21. 7. Walsh EA, Kirkpatrick JB, Rutherford SD, Smith DC, Sogin M, D’Hondt S. Bacterial diversity and community composition from seasurface to subseafloor. ISME J. 2016; 10: 979-989. 8. Taylor P, Tiquia SM, Davis D, Hadid H, Kasparian S, Ismail M, et al. Halophilic and halotolerant bacteria from river waters and shallow groundwater along the Rouge River of Southeastern Michigan. Environ Technol. 2010; 37-41. 9. Csonka LN. Physiological and genetic responses of bacteria to osmotic stress. Microbiol Rev. 1989; 53: 121-147. 10. Karpiński TM. Marine macrolides with antibacterial and/or antifungal activity. Mar Drugs. 2019; 17(4): 241. 11. Letchumanan V, Chan KG, Lee LH. Vibrio parahaemolyticus: a review on the pathogenesis, prevalence, and advance molecular identification techniques. Front Microbiol. 2014; 5: 1-13. 12. Gozari M, Alborz M, El-Seedi HR, Jassbi AR. Chemistry, biosynthesis and biological activity of terpenoids and meroterpenoids in bacteria and fungi isolated from different marine habitats. Eur J Med Chem. 2020; 112957. 13. Lafarga T, Acién-Fernández FG, Garcia-Vaquero M. Bioactive peptides and carbohydrates from seaweed for food applications: Natural occurrence, isolation, purification, and identification. Algal Res. 2020; 48: 101909. 14. Ganesan AR, Saravana Guru M, Balasubramanian B, Mohan K, Chao Liu W, Valan Arasu M, et al. Biopolymer from edible marine invertebrates: a potential functional food. J King Saud Univ Sci. 2020; 32: 1772-1777. 15. Rizzo C, Lo Giudice A. Marine invertebrates: underexplored sources of bacteria producing biologically active molecules. Diversity. 2018; 10: 52. 16. Jimenez-Lopez C, Pereira AG, Lourenço-Lopes C, Garcia-Oliveira P, Cassani L, Fraga-Corral, M, et al. Main bioactive phenolic compounds in marine algae and their mechanisms of action supporting potential health benefits. Food Chem. 2021; 341: 128262. 17. Hannan MA, Sohag AAM, Dash R, Haque MN, Mohibbullah M, Oktaviani DF, et al. Phytosterols of marine algae: Insights into the potential health benefits and molecular pharmacology. Phytomedicine. 2020; 69: 153201. 18. Selvin J, Lipton AP. Biopotentials of secondary metabolites isolated from marine sponges. Hydrobiologia. 2004; 513: 231-238. 19. Anjum K, Abbas SQ, Shah SAA, Akhter N, Batool S, Hassan SSU. Marine sponges as a drug treasure. Biomol Ther. 2016; 24: 347-362. 20. Tourón N, Elkhalfi B, Yassine SM, Chabir R, Errachidi F, Abdelaziz S. Rheological and antioxidant characterization of chitin and chitosan extracted with different acids. J Chitin Chitosan Sci. 2016; 4 (1): 41-45. 21. Tamadoni Jahromi S, Barzkar N. Marine bacterial chitinase as sources of energy, ecofriendly agent, and industrial biocatalyst. Int J Biol Macromol. 2018; 20: 2147-2154. 22. Murray PM, Moane S, Collins C, Beletskaya T, Thomas OP, Duarte AWF, et al. Sustainable production of biologically active molecules of marine based origin. N Biotechnol. 2013; 30: 839-850. 23. Bernstein PS. The role of lutein and zeaxanthin in protection against age-related macular degeneration. Acta Horticulturae. 2015; 1106: 153-159. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 132 European Journal of Biological Research 2021; 11(1): 122-133 24. Murillo AG, Hu S, Fernandez ML. Zeaxanthin: metabolism, properties, and antioxidant protection of eyes, heart, liver, and skin. Antioxidants. 2019; 8: 1-18 25. Suseela MR, Kiran T. Haematococcus pluvialis - a green alga, richest natural source of astaxanthin. Curr Sci. 2006; 90(12): 1602-1603. 26. Fakhri S, Aneva IY, Farzaei MH Sobarzo-Sánchez E. The neuroprotective effects of astaxanthin: Therapeutic targets and clinical perspective. Molecules. 2019; 24: 1-19. 27. Karpiński TM, Adamczak A. Fucoxanthin - an antibacterial carotenoid. Antioxidants. 2019; 8(8): 239. 28. Kokoulin MS, Kuzmich AS, Romanenko LA, Menchinskaya ES, Mikhailov VV, Chernikov OV. Sulfated O- polysaccharide with anticancer activity from the marine bacterium Poseidonocella sedimentorum KMM 9023T. Carbohydr Polym. 2018; 202: 157-163. 29. Kokoulin MS, Kuzmich AS, Kalinovsky AI, Tomshich SV, Romanenko LA, Mikhailov VV, et al. Structure and anticancer activity of sulfated O-polysaccharide from marine bacterium Cobetia litoralis KMM 3880T. Carbohydr Polym. 2016; 154: 55-61. 30. Ruocco N, Costantini S, Guariniello S, Costantini M. Polysaccharides from the marine environment with pharmacological, cosmeceutical and nutraceutical potential. Molecules. 2016; 21: 1-16. 31. Hussain A, Zia KM, Tabasum S, Noreen A, Ali M, Iqbal R, Zuber M. Blends and composites of exopolysaccharides; properties and applications: a review. Int J Biol Macromol. 2017; 94: 10-27. 32. Wang KL, Wu ZH, Wang Y, Wang CY, Xu Y. Mini-review : antifouling natural products from marine microorganisms and their synthetic analogs. Mar Drugs. 2017; 15: 266. 33. Rodrigues S, Paillard C, Dufour A, Bazire A. Antibiofilm activity of the marine bacterium Pseudoalteromonas sp. 3J6 against Vibrio tapetis, the causative agent of Brown Ring Disease. Probiotics Antimicr Proteins. 2014; 7: 45-51. 34. Klein GL, Soum-Soutéra E, Guede Z, Bazire A, Compère C, Dufour A. The anti-biofilm activity secreted by a marine Pseudoalteromonas strain. Biofouling. 2011; 27: 931-940. 35. Satheesh S, Ba-Akdah MA, Al-Sofyani AA. Natural antifouling compound production by microbes associated with marine macroorganisms – a review. Electr J Biotechnol. 2016; 21: 26-35. 36. Tortorella E, Tedesco P, Esposito FP, January GG, Fani R, Jaspars M, De Pascale D. Antibiotics from deep-sea microorganisms: Current discoveries and perspectives. Mar Drugs. 2018; 16: 1-16. 37. Liaw CC, Chen PC, Shih CJ, Tseng SP, Lai YM, Hsu CH, et al. Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp. QWI-06 using mass-spectrometry-based metabolomics approach. Sci Rep. 2015; 5: 1-11. 38. Sutherland IW. The biofilm matrix - an immobilized but dynamic microbial environment. Trends Microbiol. 2001; 9: 222-227. 39. Jorquera MA, Riquelme CE, Loyola LA, Muñoz LF. Production of bactericidal substances by a marine vibrio isolated from cultures of the scallop Argopecten purpuratus. Aquac Int. 2000; 7: 433-448. 40. Satheesh S, Ba-Akdah MA, Al-Sofyani AA. Natural antifouling compound production by microbes associated with marine macroorganisms - a review. Electron J Biotechnol. 2016; 21: 26-35. 41. Mohan K, Ravichandran S, Muralisankar T, Uthayakumar V, Chandirasekar R, Seedevi P, et al. Application of marine-derived polysaccharides as immunostimulants in aquaculture: A review of current knowledge and further perspectives. Fish Shellfish Immunol. 2019; 86: 1177-1193. 42. Qian PY, Lau SCK, Dahms HU, Dobretsov S, Harder T. Marine biofilms as mediators of colonization by marine macroorganisms: Implications for antifouling and aquaculture. Mar Biotechnol. 2007; 9: 399-410. Chbel et al. Marine biomolecules: a promising approach in therapy and biotechnology 133 European Journal of Biological Research 2021; 11(1): 122-133 43. Pradeep B, Pandey PK, Ayyappan S. Effect of probiotic and antibiotics on water quality and bacterial flora. J Inland Fish Soc India. 2003; 35(2): 68-72. 44. Mizan MFR, Jahid IK, Ha SD. Microbial biofilms in seafood: A food-hygiene challenge. Food Microbiol. 2015; 49: 41-55. 45. Radford S, States U. Sources of contamination in food. Encyclopedia of Food Security and Sustainability. Elsevier. 2018. 46. Vitale M, Schillaci D. Food processing and foodborne illness. In: Reference Module in Food Science. Elsevier. 2016; 1-9. 47. Cole DW, Cole R, Gaydos SJ, Gray J, Hyland G, Jacques ML, et al. Aquaculture: environmental, toxicological, and health issues. Int J Hyg Environ Health. 2009; 212: 369-377. 48. Yebra DM, Kiil S, Dam-Johansen K. Antifouling technology - past, present and future steps towards efficient and environmentally friendly antifouling coatings. Prog Org Coat. 2004; 50: 75-104. 49. Fusetani N. Biofouling and antifouling. Nat Prod Rep. 2004; 21: 94-104. 50. Hamza F, Satpute S, Banpurkar A, Kumar AR, Zinjarde S. Biosurfactant from a marine bacterium disrupts biofilms of pathogenic bacteria in a tropical aquaculture system. FEMS Microbiol Ecol. 2017; 93: 1-11.