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.

Natural Products

The story of bioactive natural products started more than 100 years ago. Their usual definition in the widest sense is chemical compounds isolated/derived from the nature i.e. living organisms such as plants, animals and microorganisms. These compounds may be derived from primary or rather secondary metabolism of these organisms [1]. Chemistry of natural products is related to the isolation, biosynthesis and structure elucidation of new products that led to new medical and crop protection agents. Due to their chemical diversity and various activities against diseases, they have been playing an important role in pharmaceutical and agricultural research [2].

Marine Micro Organism

Marine microorganisms have become an important point of study in the search for novel microbial products. Today both academic and industrial interest in marine microorganism is on the rise, because of the growing number of unique, biologically active metabolites reported from marine organisms [3].

The marine bacteria are one such resource for the exploration of new bioactive metabolite that are focused very recently. Marine microorganisms encompass a complex and diverse assemblage of microscopic life forms and occur through oceans, including environments of environments of extreme pressure, salinity and temperature. Marine microbes have developed unique metabolic and physiological capabilities that not only ensure survival in a great variety of extreme habitats, but also offer the potential for the production of metabolites which are not observed from terrestrial microorganisms.

Early reports indicated that marine microorganisms represent a resource of novel compounds [4]. They showed that marine bacteria produce antimicrobial agents in addition to was shown that sea water has bactericidal properties and its suspected that the activity due, to the production of antibiotic by planktonic algae [5] and by bacteria [6]. Deposit this early evidence, relatively little research has been directed towards the study of the natural product from marine microorganisms. They are capable of producing unusual natural products that are not observed from the terrestrial sources. Many of these compounds have antibiotic and other biological activates and it is clear that greatest investment in the development of marine microbiology as a resource for novel metabolite.

Actinobacteria are exciting structures inhabiting almost all possible niches [7]. They are gram-positive firmicutes with high GC content [8,9]. These prokaryotes are filamentous in nature and are considered as an intermediate group between bacteria and fungi [10]. Actinobacteria especially Streptomyces are free-living saprophytes found predominantly in the soil [11] and constitutes 50% of the total actinomycetes population [12].

Classification of Actinomycetes

According to the conventional classification systems of various authors [13,14], the species of actinomycetes are grouped together in separate genera or families chiefly on the basis of their morphological and ecological characteristics. However, studies of Romano and Sohler, [15], Romano and Nickerson and Cummins and Harris, on the cell wall composition it was classified into four common genera namely Actinomyces, Micromonospora, Nocardia and Streptomyces. They have explained the importance of cell wall analysis for the characterization of actinomycetes. The taxonomic classification of actinomycetes is determined on the basis of morphological and chemotaxonomic characterization as described by Kock et al., [16]. All genera of actinomycetes have the same general type of cell wall compositions as gram-positive bacteria, having three or four amino acids, glucosamine, muramicacid, diaminopimelicaacid and sugars. However, Goodfellow, [17] and Embley and Stackebrandt, [9], have separated the actinomycetes into different genera on the basis of morphological, chemical and molecular systematic and microbiological criteria.

Actinomycetes from Marine Sediments

Streptomyces spp. BD21-2 isolated from a shallow water sediment sample collected from Kailua Beach, Oahu, Hawaii produced an antimicrobial ester bonactin that showed antimicrobial activity against Gram-positive and Gram-negative bacteria [18]. Two quinone antibiotics, himalomycins A and B were found to be present in ethyl acetate extract of Streptomyces spp. B6921 isolated from coastal site of Mauritius (Indian Ocean) that showed activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Streptomyces viridochromogenes (Tü 57) [19], Verrucosispora strain AB-18-032, isolated from bottom of Japanese Sea was found to produce, a polycyclic polyketide abyssomicin C. It targets pamino benzoate (PABA) biosynthesis and therefore inhibits folic acid biosynthesis in clinical isolates of multidrug-resistant (MDR) bacteria and vancomycin resistantS. Aureus [20]. Sub tidal sediment samples collected from the Bismarck and the Solomon Sea off the coast of Papua New Guinea revealed the presence of 102 actinomycetes along with two new genera of family Micromonospo raceae that showed activity against MDR Gram-positive bacteria [21].

The Streptomyces species (NPS008187) isolated from sediment of Alaska Sea, also showed antibacterial activity attributed to the presence of three new pyrrolosesquiterpenes, glyciapyrroles A, B and C [22], Streptomyces strain B8005 and B4842 from sediment of the Laguna de Terminos at the Gulf of Mexico were reported [23], for antibacterial activity. Strain B8005was found to produce three antibiotics, resistomycin, tetracenomycin and resistoflavin that act against E. coli, S. viridochromogenes (Tü 57), S. aureus, Candida albicans, Mucormiehei and the microalga Chlorellavulgaris. The inhibitory activity of strain B4842 against B. subtilis, S. aureus, E. coli and C. albicans was attributed to the presence of resistoflavin methylether and resistomycin in the extract. Sediment samples collected from California, located along pacific coast of United States were reported to be rich in antagonistic actinomycetes Streptomycesnodosus (NPS007994) isolated from Scripps Canyon,La Jolla, California, showed antimicrobial activity against both drug-sensitive and resistant Gram-positive bacteria which is attributed to the presence of lajollamycin antibiotic [24]. 

In an another study the presence of Streptomyces strain CNQ-418which produces marinopyrroles was also reported from LaJolla, (California) that showed potent activities against methicillin resistant S. aureus (MRSA). Marinispora, a novel strain of a marine actinomycetes was isolated from another coast of San Diego (South California) which produced broad spectrum lynamicins that showed activity against both Gram positive and Gram-negative bacteria and was found to be effective against MRSA and vancomycin-resistant Enterococcus faecium [25]. The Streptomyces species Merv8102 isolated from sediment samples of Paltium coast on the Mediterranean Sea of Egypt produced a novel triazolopyrimidine antibiotic, essramycin that showed antibacterial activity against Gram-positive and Gram negative bacteria [26]. Marine sediment samples from different places at Anyer, a town in Banten province of Indonesia situated on West Coast, Java showed the presence of twenty-nine actinomycetes isolates that produced active compound against Gram-positive and Gram-negative bacteria [27]. Sediment samples collected from near the sea side in Bigeum Island, South west coast in South Korea also revealed the presence of actinomycetes colonies of which majority of isolates belonging to the genus Streptomyces showed very high antimicrobial activity [28].

South India is also known to be rich in actinomycetes diversity and is continuously explored for the isolation of antagonistic actinomycetes. Fifty-one strains of antagonistic actinomycetes from the littoral sediments of Parangipettai (South India) were reported of which eleven strains showed good antibiotic activity and were identified as members of genus Streptomyces and Nocardia [29]. A halophilic Actinopolyspora species AH1 isolated from Alibagcoast, Maharashtra, India showed antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis and antifungal activities against Fusarium oxysporum, Aspergillusniger, A. fumigatus, A. flavus, Trichoderma and Penicillium species [13]. Many sediment samples collected from regions around Bay of Bengal also revealed the presence of antagonistic actinomycetes. Eighty strains of actinomycetes from the sediments of the Bay of Bengal near Machilipatnam were isolated, of which seven isolates exhibited broad-spectrum antimicrobial activity [30]. Streptomyces chinaensis AUBN/7 was reported to produce 1-hydroxy-1norresistomycinand resistoflavin that showed weak 1antibacterial activities against Gram-positive and Gram-negative bacteria and also showed cytotoxicity against cell lines HepG2 (hepatic carcinoma) andHMO2 (gastric adenocarcinoma) [31]. 

In 2015, isolation of eighty-eight actinomycetes from areas near islands of the Andaman Coast of the Bay of Bengal were reported, of which most promising antibacterial activity was shown by Streptomyces, Micromonospora, Nocardia, Streptoverticilium and Saccharopolyspora. Streptomyces species BT 606 and BT 652 were active against Pseudomonas aeruginosa and S. aureus [32]. In another study the presence of antagonistic Streptomyces as dominating genus was also reported from Andaman Coast [33]. Marine actinomycete, Nocardiopsis sp. VITSVK 5 (FJ973467) was isolated from samples collected at the Puducherry coast on East of South India and tested for its antibacterial activity in three different solvent extracts and it was reported that the petroleum ether extract showed significant activity against E. coli, P.aeruginosa, Klebsiella pneumoniae, E. faecalis, Bacillus cereus and S. aureus where the ethyl acetate and chloroform extract showed antifungal activity [34]. In another study fifty actinomycete strains were isolated from sediments of Puducherry coast and were screened for antimicrobial, cytotoxicity and hemolytic activity against selected bacterial and fungal pathogens. It was reported that 24% of isolates belonging to genera Streptomyces, Micromonospora, Actinopolyspora and Saccharopolyspora showed significant antimicrobial activity against B. subtilis, S.aureus, E. coli and K. pneumoniae [35]. Streptomyces was found to be dominant genus among seventy-eight isolates of marine sediments collected from Bay of Bengal near Pudimadaka coast of Andhra Pradesh, India with promising antibacterial and antifungal activities of the genus Rhodococcus and Streptomyces [36]. 

Actinomycete strain DVR D4identified as Amycolatopsis alba from marine sediment samples from Visakhapatnam coast of Bay of Bengal, produced a cytotoxic compound, pyridinium salt antibiotic, 1-(10-aminodecyl) pyridinium which was potent cytotoxic activity against a few cell lines in vitro and also exhibited antibacterial activities against Gram positive and Gram-negative bacteria [37]. Streptomyces coeruleorubidus spp. was also isolated from a similar environment of Visakhapatnam coast that exhibited broad spectrum of antimicrobial activity against the pathogenic bacteria and fungi [38].

Production of Secondary Metabolites

Terpenes, which are compounds derived from isoprene units, are widely spread throughout nature, mainly in plants as constituents of essential oils. For his contribution to the identification and characterization of terpenes from essential oils, Geheimrat Otto Wallach was awarded with the Nobel Prize in Chemistry in 1910. More than 25,000 individual terpenes and terpenoids, their oxygenated derivatives, are known, which makes this probably the largest group of natural products. 

Majority of known terpenes are derived from terrestrial sources, in particular from plants and fungi. Studies describing the biotransformation using enzymes, cell extracts or whole cells of bacteria, cyanobacteria, yeasts and microalgae De Carvalho, 2009. However, marine terpenes have been scarcely studied and the knowledge of the biochemical processes involved in their synthesis is still limited except for a few algae and marine invertebrates. Terpenes have a variety of roles in mediating antagonistic and beneficial interactions among organisms and physiological functions [39], including membrane stabilization, anti-oxidant properties, signalling and protection.

Fermentation Process for Metabolites Production

Actinomycetes are high G+C content Gram-positive bacteria with an unparalleled ability to produce diverse secondary metabolites [40]. Optimization of fermentation conditions [32] can increase the production of secondary metabolites by several folds [32,41,42]. The synthesis of secondary metabolites begins when growth is slowing or stopped [43,44], so secondary metabolite production can be repressed by readily available carbon source, abundant nitrogen or high levels of phosphorous; all of which contribute in keeping the actinomycetes actively growing [45]. Therefore, in the preparatory (lag) phase, growth is very slow and the regulatory proteins are synthesized on the basis of new information. In the exponential or growth (log) phase, microbial growth is intensive, but the production of secondary metabolites is still low.

The transition phase is the one, in which the growth rate and protein synthesis are slowed down; enzymes of the secondary metabolism are intensively synthesized and secondary metabolite production starts. In the production phase, the growth rate is decreased, dry weight is constant and secondary metabolite production is highest. On the other hand, to reach a high secondary metabolites production, a sufficient biomass yield accomplished in a short period (e.g., short log phase) is necessary [43].The production of secondary metabolites in actinomycetes is greatly influenced by various fermentation parameters such as available [42,44], pH [32], partial pressure of oxygen (pO2) [45], temperature [32], agitation [41], mineral salts [46], metal ions [32], precursors, inducers [45,47,48] and inhibitors [43], which often vary from organism to organism [45,49].

Actinomycetes that produce secondary metabolites often have the potential to produce various compounds from a single strain [18]. The molecular basis for this well-known observation has been confirmed by several sequencing projects of different microorganisms [25]. In spite of well-known examples about induction of a selected biosynthesis (e.g., by high- or low-phosphate cultivation media), no overview about the potential in this field for determining natural products has been reported suggesting an interesting possibility for research. Interestingly, Hong et al. [25], investigated the systematic alteration of easily accessible cultivation parameters (i.e., media composition, aeration, culture vessel, addition of enzyme inhibitors) in order to increase the number of secondary metabolites available from one microbial source. They termed this way of revealing nature’s chemical diversity the “OSMAC (One Strain Many Compounds) approach” and using it they were able to isolate up to 20 different metabolites with yields up to 2.6gL −1 from a single organism [50]. These compounds covered nearly all major natural product families and in some cases the high production titer opens new possibilities for semi-synthetic Methods to produce even more chemical diversity of elected compounds. The OSMAC approach offers a good alternative to industrial high-throughput screening that focuses on the active principle in a distinct bioassay [41], Secondary metabolites from actinomycetes.

Synthesis of Antibiotics

Antibiotics are synthesized by pathways, which are often connected and influenced by primary metabolism. The intermediate metabolism from the primary metabolism serves as the precursor for the biosynthesis of the antibiotics. In fact the composition of the culture media is closely connected with the metabolic capacity of the producing organism, which greatly influences the production of antibiotics [36,51]. Most of the antibiotic compounds are synthesized as secondary metabolites [20]. Antibiotics are produced transiently by the culture over the period preceding sporulation and Streptomycetes have been reported to accumulate large storage compounds in nutrient limiting conditions. 

The growth of Streptomyces globisporus (ATCC21553), mutanolysin biosynthesis and pigment production were stimulated by the addition of bacterial cell wall to the culture medium. The increased bacteriolytic activity in the supernatant was correlated with an increased de novo synthesis of mutanolysin, which was brought about by enhanced transcription of mutanolysin gene in the presence of the bacterial cell wall at the concentration of 6 mg/ml. The stimulation could be achieved independently in the growth phase of the Streptomyces strain [47]. 

The carbon building block for antibiotic biosynthesis such as acetate propionate has been reported to originate from both hydrophobic aninoacids such as valine, isoleucine and lecuine [52]. The biosynthesis of secondary metabolites has been investigated thoroughly by biochemical and genetic analyses and many different pathways have been characterized. More than 5% of the genes of Streptomyces appear to be involved in the production of small molecule [53]. There is strong indication that pathway specific regulatory genes genetically linked to biosynthetic gene cluster activate transcription of the genes for antibiotic biosynthesis. A cluster of genes involved in jadomycin B biosysnthesis has been cloned and has been shown by nucleotide analysis to bear a close relationship to known type-II polyketide synthase gene cluster [54]. The prevalence of multiple secondary metabolite production in streptokmuyces is the synergy or contingency action of individual metabolites against biological competitors. The co-production of synergistically acting antibiotic and contingently acting siderophore, the co-production of β-lactamase antibiotic and β-lactamase inhibitiors, the co-production of type-A and Type-B streptogramins and the co-regulated production and independent uptake of structurally different distinct siderophores was reported in Streptomyces sp. [30]. Further it is concluded that the synthesis of two or more secondary metabolites that act synergistically and contingently against biological competitors is due to the synergistic and contingency driving force.

The production of two chemically different metabolites that act either synergistically against target organism has already emphasized. Synergistic metabolites have a greater antibiotic activity against competitors in combination than the sum of their individual antibiotic activities, whereas contingently acting metabolites possess similar biological activity [30]. Combination of the β-lactum and β-lactamase inhibitors is effective against the β-lactum resistant bacteria in comparison with β-lactum antibiotics alone. This is because of the synergistic action of these metabolites.

Clavulanic acid [55], is a natural inhibitor of β-lactamase and the genetics and biochemistry of its synthesis have been extensively studies in S. clauligerus [16]. The actinomycetes also produce several other β-lactum compounds including a number of structurally related clavams [56], which are antipodal to clavulanic acid and are not β-lactatamase inhibitors. The early stps of clavulanic acid and clavam biosynthesis are common but the pathway to these two structurally related metabolites diverges at clavaminic acid [16]. In contrast, the cephamycin is biosynthesized by a pathway that is mechanistically different from that of the clavams and clavulanic acid [16]. The clavulanic acid gene cluster is directly adjacent to the cephamycin cluster on the chromosome of S. clavuligerus, Streptomyces jumojinensis and Strephtomyces katsurahamaner. Such super clustering would be expected for gene clusters that direct the production of metabolites that act synergistically to benefit the producing organisms. 

Streptogramins are pairs of structurally unrelated antibiotics that synergistically inhibit bacterial ribosomal protein synthesis at the peptidyl transfer step. The type A streptogramins (e.g. pristinamycin II, viriginiamycin M1 [47], are assembled through mixed polyketide/non ribosomal peptide pathway, whereas the type B strptogramins (e.g. pristiamycin 1A) [36], are non ribosomally synthesized peptides that contains several unusual non proteino generic amino acids. Several other Streptomyces such as S. mitakaensis, Streptomyces graminofaeciens and Streptomyces lividans have been reported to co-produce dissimilar type-A and Type-B streptogramins. No species is known to produce only on type of streptogramins and the type-A or Type-B streptogramins alone is bacteriostatic but when these two are combined they exhibit bactericidal activity. The increase in antibacterial efficacy has been shown to originate from synergistic binding of the type-A and Type-B streptogramins to distinct sites on the ribosome.

The well-known property of many Strptomyces spp. To produce multi-antibiotics or other secondary metabolites has attracted much recent attention because analysis of the recently completed S. coelicolor and S. avermitilis genome sequences has suggested that this ability may be far greater than was previously thought. Clear evidences are emerging from the recent literature suggest that two driving forces for the evolution of this phenomenon may be synergistic and contingent action against biological competition, which Streptomyces spp. are not able to evade in their saprophytic lifestyle because of lack of motility. As the study of Strptomycetes secondary metabolism continues, it is anticipated that many more cases of two or more structurally distinct metabolites that can act synergistically or contingently against biological co-protection will be discovered [37].

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