Abstract
Marine actinobacteria are the most economically as well as biotechnologically valuable prokaryotes. Representative genera of marine actinobacteria include Actinomadura, Aeromicrobium, Dietzia, Gordonia, Marinophilus, Micromonospora, Nonomuraea, Rhodococcus, Saccharomonospora, Saccharopolyspora, Salinispora, Streptomyces, Solwaraspora, Williamsia, Verrucosispora and several others. Among the genera of marine actinobacteria, the genus Streptomyces is represented in nature by the largest number of species and varieties, which differ greatly in their morphology, physiology, and biochemical activities. Marine Streptomyces occur in different biological sources such as fishes, molluscs, sponges, seaweeds and mangroves, besides seawater and sediments. In this review an evaluation is made on the present state of research on marine Streptomyces and its perspectives. The highlights include the production of metabolites such as antibiotics, anticancer compounds, enzymes, enzyme inhibitors and pigments by marine Streptomyces and their application as single cell protein and as probiotics in aquaculture. The marine environment contains a wide range of distinct Streptomyces that are not present in the terrestrial environment. With increasing advancement in science and technology, there would be greater demands in future for new bioactive compounds synthesised by Streptomyces from various marine sources.
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Introduction
Actinobacteria represents one of the largest taxonomic units among the 18 major lineages currently recognised within the domain Bacteria, including five subclasses and 14 suborders (Stackebrandt 2000). Among the five subclasses, actinobacteria—bacteria belonging to the Order Actinomycetales (commonly called actinomycetes)—account for approximately 7,000 of the metabolites reported in the Dictionary of Natural Products. Actinomycetes have a high GC content in their deoxyribonucleic acid (DNA) and grow as aerial mycelia (Yoshida et al. 2008). They are responsible for the production of about half of the discovered secondary metabolites (Bull 2004; Berdy 2005), notably antibiotics (Strohl 2004), antitumour agents (Olano et al. 2009), immunosuppressive agents (Mann 2001) and enzymes (Pecznska-Czoch and Mordarski 1988; Oldfield et al. 1998). A large number of actinomycetes have been isolated and screened from soil in the past few decades (Williams et al. 1989). Recently, the rate of discovery of new metabolites from terrestrial actinomycetes has decreased, whereas the rate of re-isolation of known compounds has increased (Fenical et al. 1999; Fenical and Jensen 2006). Thus, it is crucial that new groups of actinomycetes from unexplored or underexploited habitats be pursued as sources of novel secondary metabolites.
The diversity of life in the terrestrial environment is extraordinary, but the greatest biodiversity occurs in the oceans (Donia and Hamann 2003). Indeed, the marine environment is a virtually untapped source of novel actinomycete diversity (Stach et al. 2003; Magarvey et al. 2004) and therefore, of new metabolites (Bull et al. 2005; Fiedler et al. 2005). The distribution of actinomycetes in the sea is largely unexplored and the presence of indigenous marine actinomycetes in the oceans remains elusive. This is partly caused by the lack of effort spent in exploring marine actinomycetes, whereas terrestrial actinomycetes have been, until recently, a successful source of secondary metabolites. Furthermore, scepticism regarding the existence of indigenous populations of marine actinomycetes arises from the fact that the terrestrial bacteria produce resistant spores that are known to be transported from land into sea, where they can remain available but dormant for many years (Bull et al. 2000). Thus, it has been frequently assumed that actinomycetes isolated from marine samples are merely of terrestrial origin.
Recent data from culture-dependent studies have shown that indigenous marine actinomycetes indeed exist in the oceans (Jensen et al. 2005a; Lam 2006). Actinomycete genera identified by cultural and molecular techniques from different marine ecological niches include Actinomadura, Actinosynnema, Amycolatopsis, Arthrobacter, Blastococcus, Brachybacterium, Corynebacterium, Dietzia, Frankia, Frigoribacterium, Geodermatophilus, Gordonia, Kitasatospora, Micromonospora, Micrococcus, Microbacterium, Mycobacterium, Nocardioides, Nocardiopsis, Nonomurea, Psuedonocardia, Rhodococcus, Saccharopolyspora, Salinispora, Serinicoccus, Solwaraspora, Streptomyces, Streptosporangium, Tsukamurella, Turicella, Verrucosispora and Williamsia (Stach et al. 2004; Jensen et al. 2005b; Ward and Bora 2006; Das et al. 2006a). Marine environmental conditions are extremely different from terrestrial ones; it is surmised that marine actinomycetes have different characteristics from those of terrestrial counterparts and therefore, might produce different types of secondary metabolites. Over the past decade, information on the diversity of actinomycetes in marine habitats has grown considerably, while the somewhat longer held interest in their ability to produce secondary metabolites has continued quite strongly (Stackebrandt et al. 1997).
Marine actinomycetes are a prolific source of secondary metabolites and the vast majority of these compounds are derived from the single genus Streptomyces. Streptomyces species are distributed widely in marine and terrestrial habitats (Pathom-aree et al. 2006) and are of commercial interest due to their unique capacity to produce novel metabolites. It was also expected that Streptomyces species will have a cosmopolitan distribution, as they produce abundant spores that are readily dispersed (Antony-Babu et al. 2008). These filamentous bacteria are well adapted to the marine environment and are able to break down complex biological polymers. The genus Streptomyces was classified under the family Streptomycetaceae, which includes Gram-positive aerobic members of the order Actinomycetales and suborder Streptomycineae within the new class Actinobacteria (Stackebrandt et al. 1997; Anderson and Wellington 2001), with a DNA G + C content of 69–78 mol%. In fact, the genus Streptomyces alone accounts for a remarkable 80% of the actinomycete natural products reported to date, a biosynthetic capacity that remains without rival in the microbial world (Watve et al. 2001).
Marine Streptomyces are widely distributed in biological sources such as fishes, molluscs, sponges, seaweeds, mangroves, besides seawater and sediments. These organisms are gaining importance not only for their taxonomic and ecological perspectives, but also for their production of novel bioactive compounds like antibiotics, enzymes, enzyme inhibitors, pigments and for their biotechnological application such as probiotics and single cell protein. In this review, the distribution of marine Streptomyces in various biological sources, their metabolite production and application in biotechnology are outlined in detail.
Metabolite production by marine Streptomyces
About 23,000 antibiotics have been discovered from microorganisms. It has been estimated that approximately 10,000 of them were isolated from actinomycetes (Okami and Hotta 1988). Actinomycetes, mainly the genus Streptomyces, have the ability to produce a wide variety of secondary metabolites as bioactive compounds, including antibiotics. The group has an enormous biosynthetic potential that remains unchallenged among other microbial groups. The immense diversity, along with its underutilisation is the fundamental reason for attracting researchers towards it for discovering novel metabolites. The genus Streptomyces is represented in nature by the largest number of species among all the genera of actinomycetes and figures over 500 species. The name Streptomyces was introduced in 1943 for the aerial mycelia-producing actinomycetes. Actinomycetes comprise about 10% of the bacteria colonising marine aggregates and can be isolated from various marine sources. Many actinomycete isolates from the depths of the oceans contain non-ribosomal polyketide synthase (NRPS) and polyketide synthase (PKS) pathways, the hallmarks of secondary metabolite production (Li and Piel 2002; Salmon et al. 2003).
Terrestrial soils have hitherto been the predominant and widely exploited source, and investigations on marine Streptomyces are few and inconclusive, though they are the important sources for new bioactive compounds (Okami 1984). During the last decade, there has been increasing number of novel metabolites possessing potent bioactivity isolated from marine-derived Streptomyces (Lam 2006; Wu et al. 2007). Many of them are cytotoxic and come from a wide variety of chemical structures such as macrolides, α-pyrones, lactones, indoles, terpenes and quinones.
The Streptomyces strains isolated from different marine sediment samples collected from Tuticorin coast, South India, exhibited inhibitory activity against fish pathogens namely Aeromonas hydrophila, Aeromonas sobria and Edwardsiella tarda (Patil et al. 2001). Around 64 cultures of Streptomyces strains were isolated from marine sediment samples of Andaman coast. Among 64 Streptomyces sp., 44 isolates showed antibacterial activity and 17 isolates showed antifungal activity. Three isolates showed very promising antagonistic activities against multi-drug resistant pathogens (Sujatha et al. 2005a). Seven strains of Streptomyces isolated from marine sediments of South China, were found to produce siderophores which inhibit the growth of Vibrio spp. in vitro and act as biocontrol agents in aquaculture (You et al. 2005). Marine S. griseorubens isolated from marine sediment of China exhibited anti-tumour activity (Ye et al. 2009). Three Streptomyces strains (DKDVIT 1, 2 and 3) isolated from the marine soil samples of Ennore coastal region of Tamil Nadu, India showed antidermatophytic activity (Lakshmipathy and Krishnan 2009).
An antifungal protein (SAP) was found in the culture supernatant of a marine Streptomyces sp. strain AP77 isolated from the seawater of Japan, which is specific for Pythium porphyrae, a causative agent of red rot disease in Porphyra spp (Woo et al. 2002). The water surface microlayer of sea is still poorly explored, although it has been shown to contain a high density of metabolically active bacteria, often called bacterioneuston. Streptomyces from the surface microlayer in the Trondheim fjord, Norway, have been isolated and characterised. The strain exhibited antagonistic activity against non-filamentous fungi and Gram-negative and Gram-positive bacteria (Hakvag et al. 2008).
A novel strain S. xiamenensis was isolated from the national mangrove reserve in Fujian Province, China. It synthesised compounds such as menaquinones, MK-9(H4) and MK-9(H6) and fatty acids (Xu et al. 2009). Streptomyces strain 23-2B was isolated from the marine shellfish Donax trunculus anatinus collected from Mediterranean Sea (El-Shatoury et al. 2009). Streptomyces 23-2B was particularly noted for its high antitumour activity against Ehrlich’s ascites carcinoma with plateau inhibitory effect, promising solid tumour selectivity and high cytotoxicity to human carcinoma of liver (HEPG2), cervix (HELA) and breast (MCF7).
Marine Streptomyces sp. (BTL7) was found to be associated with the marine sponge Dendrilla nigra and synthesised antibacterial substances. The findings suggested that secondary metabolites of Dendrilla nigra might have been synthesised by the associated bacterial endosymbionts (Selvin et al. 2004). About 74% of Streptomyces isolates were found to be associated with the sponge Hymeniacidon perleve (Zhang et al. 2006). In another report, isolation of marine Streptomyces associated with sponges Callyspongia diffusa were screened for antimicrobial activity against pathogenic bacteria and fungi (Gandhimathi et al. 2008). An exploration on the functional role of the antagonistic producer strain S. dendra sp. nov. MSI051 showed hypothetical factors including the antagonistic potential of MSI051 against biofilm bacteria and a ubiquitous defence enzyme phospholipase A2 (PLA2) in host sponge as well as in bacterial symbiont MSI051. Isolate MSI051 also showed a broad spectrum of antibacterial activity. Polyketide synthase gene type II in MSI051 ultimately evidenced the antagonistic potential. Antimicrobial activity was found to be positively skewed towards biofilm bacteria. All factors imply the functional role of MSI051 in the protection of host sponge against fouling processes (Selvin 2009). Recently about 94 isolates of Streptomyces were found to be associated with four marine sponges namely Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis collected from South West coast of India. These strains showed antibacterial and antifungal activities (Dharmaraj and Sumantha 2009).
Marine Streptomyces have proven to be efficient producers of bioactive metabolites which have a wide range of activities such as antibacterial, antifungal, antitumour, anticancer, cytotoxic, etc. Depending on the chemical nature, these bioactive substances are classified as follows:
Peptides
Peptides are short polymers of amino acids. Most of the Streptomyces peptides are cyclic and contain further rare structural elements such as chromophores or uncommon amino acids. The peptides include cyclomarin A (1), cyclic in nature and produced by an unidentified marine Streptomyces sp. Cyclomarins showed anti-inflammatory and antiviral activities (Renner et al. 1999). Piperazimycins A-C (2) are cytotoxic hexadepsipeptides isolated from the fermentation broth of a Streptomyces sp. Piperazimycin A exhibited potent in vitro cytotoxicity against multiple tumour cell lines (Miller et al. 2007). Another new 3-(4-hydroxybenzyl) piperazine-2, 5-dione was isolated from the marine actinobacterium Streptomyces strain KMM7210. The cytotoxic activities of the compounds were estimated from their effects on sperm and eggs of the sea urchin Strongylocentrotus intermedius (Sobolevskaya et al. 2007). Allophycocyanin is one of the most important marine active peptides. Previous studies suggested that allophycocyanin could remarkably inhibit the S-180 carcinoma in mice, indicating its potential pharmaceutical use. This was isolated from marine Streptomyces strain M097 (Hou et al. 2006). Two cyclic peptides dehydroxy-nocardamine and desmethylenyl-nocardamine along with nocardamine (3) have been isolated from a Streptomyces sp. which was obtained from an unidentified marine sponge. These new compounds exhibited weak inhibition against the enzyme sortase B (Lee et al. 2005). Salinamides A and B (4) are bicyclic depsipeptides produced by a Streptomyces sp. CNB-091 isolated from the jelly fish Cassiopeia xamachana. These metabolites are useful as antibiotic and anti-inflammatory agents (Moore et al. 1999). Two new dipeptide derivatives, 8-amino-[1, 4]diazonane-2, 5-dione (5) and leucyl-4-hydroxyproline (6) were isolated from marine S. acrimycini and their biological roles are yet to be determined (Hernandez et al. 2004). Various peptides produced by marine Streptomyces are displayed in Fig. 1.
Quinones
Quinones are compounds having a fully conjugated cyclic dione structure. They are common constituents of biologically relevant molecules. Marine Streptomyces are especially rich in highly biologically active quinones. Recent examples are the complex C-glycosides himalomycins A (7) and B (8), anthraquinones with the rare fridamycin E chromophore, a precursor of the anthracycline antibiotics. They were obtained from Streptomyces sp. 6921 isolated from marine sediments of Mauritius and exhibited strong antibacterial activity (Maskey et al. 2003). Anthraquinone, 1,8-dihydroxy 2-ethyl 3-methyl anthraquinone was isolated from marine Streptomyces sp. FX-58. This compound showed cytotoxic activities (Huang et al. 2006). Tetracenomycin D (9) is an anthraquinone antibiotic produced by S. corchorusii AUBN (1)/7 (Adinarayana et al. 2006). It showed cytotoxicity against cell line HMO2 (gastric adenocarcinoma) and HepG2 (hepatic carcinoma) and possesses weak antibacterial activities against Gram-positive and Gram-negative bacteria. Komodoquinone A (10) and its chromophore, komodoquinone B (11) belong to the anthracycline antibiotics. They were isolated from the fermentation broth of Streptomyces sp. KS3 and showed neuritogenic activity. They induce cell differentiation in the neuroblastoma cell line, Neuro2A and arrests cell cycle at the G1 phase (Itoh et al. 2003). The benzopyrene quinones include resistomycin and resistoflavine. Resistomycin (12) is produced by S. corchorusii AUBN (1)/7 (Shiono et al. 2002). This is an inhibitor of HIV-1 protease. Resistoflavine (13) is produced by S. chibaensis AUBN (1)/7 (Kock et al. 2005; Gorajana et al. 2006). The structures of the quinones discussed above are displayed in Fig. 2.
Macrolides
The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars may be attached. Generally, macrolides are protein synthesis inhibitors. The Streptomyces sp. M491, a marine actinobacterium produces a macrolide antibiotic named chalcomycin (14) and also some terpenes (Wu et al. 2007). Another macrolide antibiotic designated as chalcomycin B (15) was isolated from the culture broth of a marine Streptomycete isolate B7064 (Asolkar et al. 2002). The chemical structures of macrolides are shown in Fig. 3.
Terpenes
Terpenes are a large and varied class of hydrocarbons. They are the major biosynthetic building blocks within nearly every living creature. Terpenes are derived biosynthetically from units of isoprene, which has the molecular formula C5H8. As chains of isoprene units are built up, the resulting terpenes are classified sequentially by size as hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, and tetraterpenes. The Streptomyces sp. NPS008187 isolated from marine sediment collected in Alaska, synthesised three new pyrrolosesquiterpenes, glyciapyrroles A (16), B (17) and C (18). They exhibited antibacterial activity (Macherla et al. 2005). Azamerone (19), a novel meroterpenoid was isolated from the saline culture of marine-derived Streptomyces. Azamerone is composed of an unprecedented chloropyranophthalazinone core with a 3-chloro 6-hydroxy 2, 2, 6-trimethylcyclohexylmethyl side chain. It appears to be the first natural product with a phthalazione ring (Cho et al. 2006a). A new sesquiterpene known as selina-4(14),7(11)-diene-8,9-diol (20) was isolated from Streptomyces sp.QD518. This compound showed anticancer properties (Wu et al. 2006). Amorphane sesquiterpenes namely 10α,11-dihydroxyamorph-4-ene (21), 10α,15-dihydroxyamorph-4-en-3-one (22) and 5α,10α,11-trihydroxyamorphan-3-one(23) are produced by Streptomyces sp. M491. The bioactivity of amorphane is unknown (Wu et al. 2007). T-Muurolol sesquiterpenes were isolated from Streptomyces strain M491 derived from marine sediment Qingdao coast, China. These sesquiterpenes of the T-muurolol family were tested for their cytotoxycity against 37 human tumour cell lines, but only 15-hydroxy-T-muurolol (24) showed moderate cytotoxic activity (Ding et al. 2009). The chemical structures of terpenes are diagrammatically shown in Fig. 4.
Tetraterpenes include carotenoids which are ubiquitous pigments synthesised by plants, fungi, algae, and bacteria. Industrially, carotenoids are used in pharmaceuticals, nutraceuticals, animal feed additives, as well as colorants in cosmetics and foods. Scientific interest in dietary carotenoids has increased in recent years because of their beneficial effects on human health, such as lowering the risk of cancer and enhancement of immune system function, which are attributed to their antioxidant potential. Carotenoid synthesis in prokaryotes occurs in a constitutive, light-induced or cryptic manner. Whereas the majority of microbes reported produce carotenoids constitutively, some organisms belonging to Myxococcus, Streptomyces, Mycobacterium, Agromyces and Sulfolobus form these pigments when the cells are illuminated. To date, the carotenoid production in Streptomyces has been performed with terrestrial strains like S. griseus (Schumann et al. 1996; Lee et al. 2001), S. setonii (Kato et al. 1995) and S. coelicolor A3 (2) (Takano et al. 2005). There was a recent report on the production of carotenoids by marine Streptomyces strain AQBWWS1 isolated from marine sponge Callyspongia diffusa (Dharmaraj et al. 2009).
Polyketides
Polyketides are a large and structurally diverse group of natural products synthesised by multifunctional or mono- or bi-functional enzymes called polyketide synthases (PKSs) by repetitive condensations of small carboxylic acid units in a manner similar to fatty acid synthesis (Staunton and Weissman 2001). Many of them are of industrial and medical importance. Some of the polyketides of industrial importance like doramectin, epirubicin and compounds like aurantimycin, chartreusin, concanamycin, kirromycin, lysolipin, polyketomycin were used for medical treatments (Weber et al. 2003). Generally in bacteria the genes required for the biosynthesis of a given polyketide are usually clustered.
The Streptomyces sp. JP95 isolated from the marine ascidian Aplidium lenticulum at Heron Island, Australia was found to biosynthesise the polyketide, griseorhodin A (25) and the biological role of the compound has not yet been determined (Li and Piel 2002). A marine inhabitant known as S. psammoticus produces a polyketide antibiotic SBR-22 (Sujatha et al. 2005b). It showed antibacterial activity against methicillin-resistant Staphylococcus aureus. Daryamides A (26), B (27) and C (28) are cytotoxic polyketides isolated from culture broth of a Streptomyces strain, CNQ-085 (Asolkar et al. 2006). These bioactive compounds showed weak to moderate cytotoxicity against the human colon carcinoma cell line HCT-116 and very weak antifungal activities against Candida albicans. Actinofuranones A (29) and B (30) were isolated from the fermentation broth of a marine bacterium related to Streptomyces genus. Actinofuranones A and B showed weak in vitro cytotoxicity against mouse splenocyte T-cells and macrophages (Cho et al. 2006b). Recently three new polyketides, phaeochromycins F (31), G, H were obtained from the culture broth of marine Streptomyces sp. DSS-18. These compounds exhibited cytotoxic effect (Li et al. 2008). The structure of polyketide compounds are displayed in Fig. 5.
Enzymes
Marine Streptomyces strains (PDK2, PDK7) isolated from South Indian coast, produced L-asparaginase and exhibited cytotoxic effect on JURKAT cells (Acute T cell leukemia) and K562 cells (chronic myelogenous leukemia) (Dhevagi and Poorani 2006). S. aurantiacus isolated from Bhitarkanika mangrove ecosystem of Orissa, India exhibited different extracellular activity like phosphate solubilisation, lipase and L-asparaginase production (Gupta et al. 2007). Streptomyces marine isolates S3, S4 and K8 showed the production of extracellular anti-leukemic enzyme L-asparaginase obtained by solid-state and submerged fermentation (Basha et al. 2009). The S. clavuligerus strain isolated from the western coast of India, exhibited the production of alkaline protease (Thumar and Singh 2007). Thermostable alkaline protease was characterised from marine S. fungicidicus MML1614 (Ramesh et al. 2009).
Marine Streptomyces sp. DA11 isolated from South China, found to be associated with sponge Craniella australiensis, produced the enzyme chitinase and showed antifungal activities against Aspergillus niger and Candida albicans (Han et al. 2009). Chitin, a linear β-1,4-linked homopolymer of N-acetylglucosamine, is one of the three most abundant polysaccharides in nature besides cellulose and starch. The antifungal activity and highly biocompatible quality make chitinase and its derivatives particularly useful for biomedical applications, such as wound healings, cartilage tissue engineering, drug delivery, and nerve generation (Shi et al. 2006; Yan et al. 2006). The biodegradable and antifungal properties of chitinase are also useful for environmental and agricultural uses, food technology and cosmetics (Goosen 1997; Rabea et al. 2003; Lin and Lin 2005).
An alginate-degrading bacterium classified as Streptomyces sp. ALG-5 was isolated from marine seaweeds of South Korea (Kim et al. 2009). Alginate lyases catalyse the degradation of alginate through β-elimination of the glycosidic bond. More than 50 alginate lyases with various substrate specificities have been isolated from algae, marine invertebrates and a wide range of microorganisms. Most alginate lyases exhibit endo-cleaving activity.
Enzyme inhibitors
Enzyme inhibitors are molecules that bind to enzymes and decrease their activity. The binding of an inhibitor can stop a substrate from entering the enzyme’s active site and/or hinder the enzyme from catalysing its reaction. Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically. These inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both. A few enzymes inhibitors have been reported from marine Streptomyces. An α-amylase inhibitor was isolated from S. corchorusii subsp. rhodomarinus. subsp. nov (Imada and Simidu 1988). Pyrizinostatin (32) is an inhibitor of pyroglutamyl peptidase, isolated from culture of Streptomyces sp. SA-2289 (Aoyagi et al. 1992). Pyrostatin A (33) and B (34) are inhibitors of N-acetyl β-glucosaminidase, produced by Streptomyces sp. SA-3501 (Aoyama et al. 1995; Imada 2004, 2005). The chemical structures of these compounds are shown in Fig. 6.
Indole compounds
Three new cytotoxic 3,6-disubstituted indoles A (35), B (36) and C (37) (Fig. 7) obtained from Streptomyces sp. BL-49-58-005 were found to be associated with Mexican marine invertebrate (Jose et al. 2003).
Piericidins
Piericidins C7 (38) and C8 (39) are the two new members of the piericidin family, isolated from a marine Streptomyces sp. Piericidins C7 and C8 (Fig. 8) showed selective cytotoxicity against rat glia cells transformed with the adenovirus E1A gene and Neuro2A mouse neuroblastoma cells (Hayakawa et al. 2007).
Trioxacarcins
Trioxacarcins are complex compounds showing high antibacterial activity against Gram-positive and Gram-negative bacteria, and some of them possess high antitumour and antimalarial activities as well. Trioxacarcin A exhibited antifungal activities. Trioxacarcin A, B and C (40) (Fig. 8) were obtained from S. ochraceus and S. bottropensis (Maskey et al. 2004). Some of these compounds possess extremely high antiplasmodial activity, which is comparable to that shown by artemisinin, the most active compound against the pathogen of malaria.
Methylpyridine
Streptokordin is a new cytotoxic compound of the methylpyridine class isolated from the culture broth of Streptomyces sp. KORDI-3238 (Jeong et al. 2006). It exhibited significant cytotoxicity against several human cancer cell lines but showed no growth inhibition against bacteria and fungi.
Marinopyrroles
Marine Streptomyces strain CNQ-418 obtained from a marine sediment sample collected near La Jolla, California (Hughes et al. 2008), produced marinopyrroles A (41) and B (42) (Fig. 8) which were densely halogenated, axially chiral metabolites that contain an uncommon bispyrrole structure. The marinopyrroles possess potent antibiotic activities against methicillin resistant-Staphylococcus aureus (MRSA).
Sisomicin
Marine Streptomyces strain GB-2 isolated from coastal soil of China produced the antibacterial substance sisomicin (43) (Fig. 9) (Lu et al. 2009).
Triazolopyrimidine
The Streptomyces sp. Merv8102 derived from sediment samples of Paltium coast on the Mediterranean Sea of Egypt produced a novel triazolopyrimidine antibiotic, essramycin (44) (Fig. 9). The compound is antibacterially active with MIC of 2–8 μg/ml against Gram-positive and Gram-negative bacteria, while it showed no antifungal activity (El-Gendy et al. 2008b).
Esters
Bonactin (45) (Fig. 9), an antimicrobial ester, isolated from the Streptomyces sp. BD21-2 obtained from marine sediment sample collected at Hawaii displayed antimicrobial activity against both Gram-positive and Gram-negative bacteria as well as antifungal activity (Schumacher et al. 2003).
Caprolactones
Two new caprolactones R-10-methyl-6-undecanolide and (6R, 10S)-10-methyl-6-dodeconolide are produced by a marine Streptomyces sp. B6007. These caprolactones showed moderate phytotoxicity and low cytotoxocity against cancer cells (Stritzke et al. 2004).
Macrocyclic lactam
Aureoverticillactam, a novel 22-atom macrocyclic lactam was isolated from S. aureoverticillaris. It showed cytotoxicity against various tumour cell lines (Mitchell et al. 2004). Lajollamycin (46) (Fig. 9), a nitro-tetraene spiro β-lactone γ-lactam antibiotic isolated from S. nodosus (NPS007994) collected in marine sediment of California showed antimicrobial activity against both drug-sensitive and resistant Gram-positive bacteria and inhibited the growth of B16-F10 tumour cells in vitro (Manam et al. 2005).
Manumycin derivatives
Chinikomycins A (47) and B (Fig. 9) are chlorine-containing aromatic manumycin derivatives. They exhibit antitumour activity against different human cancer cell lines, but are inactive as antiviral, antimicrobial and phytotoxic agents. These compounds are produced by Streptomyces strain MO45 (Li et al. 2005).
Streptochlorin
Streptochlorin (48) (Fig. 9) was isolated from the fermentation broth of a marine Streptomyces strain 04DH110. Streptochlorin exhibited significant antiproliferative activity against human cultured cell lines (Jae et al. 2007).
Chartreusin
The marine Streptomycete isolates B5525 and B5342 produced chartreusin 2″-monoacetate (49) (Fig. 10). Chartreusin was not only antibacterially active, but also showed antitumour activity against different human cell lines (Maskey et al. 2002).
Butenolides
Butenolides, a family of α,β-unsaturated lactones, are often encountered among fungi, bacteria, and gorgonians. Their saturated analogues act as signalling substances in bacteria and enhance spore formation of Streptomycetes or induce metabolite production. Four types of butenolides were found in the extracts from the Streptomycete strains B 5632 and B 3497 (Mukku et al. 2000). The butenolides include (4S)-4,10-dihydroxy-10-methyl-undec-2-en-1,4-olide (50), (4S)-4,10-dihydroxy-10-methyl-dodec-2-en-1,4-olide (51) and the mixture of 3 and 4, (4S)-4,11-dihydroxy-10-methyl-dodec-2-en-1,4-olides (52) (Fig. 10).
Alkaloids
Aburatubolactams A (53), B (54) and C (55) (Fig. 10) were isolated from the marine Streptomyces sp. SCRC-A20. They were able to inhibit superoxide anion generation. Superoxide anions are thought to be closely associated with inflammation, cancer, and aging (Bae et al. 1996; Yamada et al. 1999).
Flavonoids
Flavonoids are polyphenolic compounds extremely common in higher plants, but very rare as bacterial metabolites. Actinoflavoside, a novel glycoside composed of a rare 2, 3, 6-trideoxy-3-amino-ribopyranoside (ristosamine) amino sugar and an aglycone reminiscent of the plant flavonoids, was isolated from the culture broth of a marine Streptomyces strain CNB-689 (Jiang et al. 1997). The structure of actinoflavoside was established by spectroscopic analysis and by chemical degradation. Actinoflavoside possesses a 5-hydroxymethyl flavonone skeleton which is different from all other flavonones known. Actinoflavoside showed only weak antibacterial activity against Gram-positive bacteria, including Staphylococcus pneumonia, S. pyrogenes, S. aureus and Micrococcus luteus. Some marine Streptomyces synthesise benzopyrone derivatives such as 7-methylcoumarin and the flavonoids, rhamnazin and cirsimaritin (El-Gendy et al. 2008a).
Isoflavonoids occur as phytochemicals of many plants. Marine Streptomyces sp. 060524 isolated from the South China Sea, capable of hydrolysing the glycosidic bond of isoflavone glycosides was isolated by detecting its β-glucosidase activity. Five isoflavone aglycones were isolated from culture filtrates and identified as genistein, glycitein, daidzein, 3′,4′,5,7-tetrahydroxyisoflavone and 3′,4′,7-trihydroxyisoflavone. The isoflavone glycoides showed strong cytotoxicity against K562 human chronic leukemia (Hu et al. 2009).
Other substances
Marine-derived Streptomyces 3320 strain collected from marine sediment of Jiaozhou Bay, China showed antitumour activity. Ten compounds, cyclo-(Ala-Leu), cyclo-(Ala-Ile), cyclo-(Ala-Val), cyclo-(Phe-Pro), cyclo-(Phe-Gly), cyclo-(Leu-Pro), 1-methyl 2,3,4-tetrahydro-carboline 3-carboxylic acid, N-(4-hydroxyphenethyl) acetamide, 4-methyoxy l-(2-hydroxy) ethylbenzene and uridine, were isolated from the fermented broth of Streptomyces 3320. Among these, compounds 6, 7, 8 and 10 showed potent cytotoxicity against the tsFT210 cells. Compounds 8, 10 also exhibited apoptosis inducing activity. Compounds 6, 7, 8 and 10 are the principal bioactive constituents responsible for the antitumour activities of marine Streptomyces 3320 (Hong et al. 2006). An antifungal compound, 4′-phenyl 1-napthyl phenyl acetamide was characterised from Streptomyces sp. DPTB16 isolated from Cuddalore coastal soil, Tamil Nadu, India (Dhanasekaran et al. 2008). Three isolates of Streptomyces (LA3L1, LA3L2 and LA3L4) were found to be symbiotic with both New Zealand and Malaysian marine invertebrates (Mahyudin 2008). Streptomyces sp. (LA3L2) showed good cytotoxicity and a new cytotoxic metabolite was isolated from a large scale extract of Streptomyces sp. (LA3L2). This metabolite was characterised as S-methyl-2,4-dihydroxy-6-isopropyl-3,5-dimethylbenzothioate and the compound was reported to contain the S-methylbenzothioate group. The other two Streptomyces sp. yielded three known cytotoxic metabolites. These were thiazostatin B from Streptomyces sp. (LA5L4) and chromomycin A2, chromomycin A3 and chromomycin 02-3D from Streptomyces sp. (LA3L1).
Biotechnological application of marine Streptomyces
Single cell protein
Streptomyces are known to produce secondary metabolites that enhance the growth of juvenile fish, shrimp and prawn. There have been reports on the application of marine Streptomyces as a SCP source, incorporated in the formulated feed and supplemented to juvenile prawns weighing about 0.130–0.160 g/body weight. The ingredients of the control feed consisted of fishmeal (14.76 g), groundnut oil cake (14.76 g), rice bran (35.24 g) with tapioca flour (35.24 g) as binder, whereas the SCP incorporated feed consist of fishmeal + Streptomyces cells (14.76 g + 165 mg) and the rest were the same as control feed. After 50 days of feeding trials, the growth parameters like feed conversion efficiency, feed conversion ratio and protein content were analysed. The prawns fed with Streptomyces-incorporated feed showed improved growth (140.54%), feed conversion efficiency (45%), and higher protein content (54.72%), whereas the prawns fed with control feed showed less growth of 89.52%, food conversion efficiency (20%) and protein content of 35.02%. The feed conversion ratio will be less for the SCP fed-prawns (2.217) than the control (5.015). Hence, among unconventional protein sources, single cell protein (SCP) of microbial origin appears to be a promising substitute for fishmeal, which can replace up to 25–50% fishmeal in aquaculture operations (Manju and Dhevendaran 1997).
Probiotics
Despite the source of several novel antibiotics, marine Streptomyces spp. have been given less attention as probiotics in aquaculture. However, it was recommended that marine Streptomyces are promising candidates to be utilised in marine aquaculture. You et al. (2005) described the potential of Streptomyces against the shrimp pathogen Vibrio spp. and recommended marine Streptomyces as potential probiotic strains due to their ability to degrade macromolecules such as starch and protein in culture pond water, to produce antimicrobial agents and to form heat- and desiccation-resistant spores. More recently, there were a few studies on the possible use of marine Streptomyces in disease prevention against aquatic pathogens. Das et al. (2006b) reported a preliminary study on the use of Streptomyces-incorporated feed as probiotic source for the growth of black tiger shrimp. Cells of Streptomyces were incorporated at different concentrations (0, 2.5, 5.0, 7.5, and 10.0 g/kg feed) in the formulated feeds, supplemented for 25 days and growth was monitored. At a concentration of 10 g, shrimp fed with Streptomyces-incorporated feed showed high growth in terms of length (15.79%) and weight (57.97%) when compared with the control [length (4.08%) and weight (32.77%)]. The growth of the tiger shrimp, Penaeus monodon, also increased with an increase in the concentration of Streptomyces in the supplemented feed.
Kumar et al. (2006) reported the antiviral property of marine Streptomyces against White Spot Syndrome Virus (WSSV) in penaeid shrimps. WSSV infection can cause cumulative mortality up to 100% within 3–10 days, thereby causing considerable economic loss to the shrimp farmers. Antibiotic extracts were obtained from the fermentation broth of twenty-five isolates of marine Streptomyces (isolated from the coastal waters of Southwest coast of India), incorporated in the formulated feeds and supplemented to the post-larvae (PL-20) of the black tiger shrimp Penaeus monodon for 2 weeks and challenged with WSSV. The pattern of post-challenge survival % (PCS %) in the 27 treatments (25 experimental and two controls) exhibited a wide range of variation from 11 to 83% during the course of the experiment. PCS % was lowest in the controls (C1—4.3%, C2—5.2%) on day 7. However, six probiotic feeds (SA 2, SA 8, SL 27, SL 33, SL 39, and SL 85) supplemented to post-larvae shrimp recorded the highest PCS % ranging between 50 and 83%. Also, severity of the infection observed on days 3, 4 and 5 in post-larvae shrimp fed with other diets was not visible in these groups. In this case, positive effect was obtained by the antibiotic extract incorporated in the feed against WSSV infected penaeid shrimps.
You et al. (2007) reported the activity of marine Streptomyces as a potential organism against biofilms produced by Vibrio spp. Nearly 88 isolates of marine Streptomyces extracts were screened against biofilms produced by various Vibrio species. Among these, 35 inhibited the biofilm formation of Vibrio harveyi, Vibrio vulnificus, and Vibrio anguillarum at a concentration of 2.5% (v/v). Thirty-three of the Streptomyces extracts dispersed the mature biofilm and six extracts inhibited the quorum-sensing system of V. harveyi by attenuating the signal molecules, N-acylated homoserine lactones’ activity. The marine Streptomyces strain A66 was able to attenuate the biofilms and also inhibit their quorum-sensing system. It is suggested that the Streptomyces strain A66 is a promising candidate to be used in marine aquaculture and is also recommended for the prevention of diseases caused by Vibrio spp.
Conclusions
The marine environment has a vast biological diversity and has been recognised as a potential source of a large number of novel chemical entities. The bioactive substances derived from marine Streptomyces are just beginning to be realised. In order to improve the future exploitation of bioactive substances from marine Streptomyces and to make the process technically and economically feasible, there are numerous parameters to follow, and these include the application of appropriate isolation media (with optimal salinity, pressure, temperature, and nutrient concentration) for the various sources from the depths of the ocean and primary screening of the fermentation broths extracts using classical methods to define the metabolites combined with techniques such as high pressure liquid chromatography with diode array detection (HPLC–DAD) for metabolite profiling, structural information through mass spectrometry and nuclear magnetic resonance (NMR) and two-dimensional (2D) NMR spectra arrays. Furthermore, molecular techniques like genome sequencing of the most promising strains and identification of cryptic biosynthetic gene clusters would greatly enhance the ability to isolate their metabolic products. There are also several techniques to maximise gene expression that include physicochemically informed (PCI) screening of the gene clusters, gene knockouts, comparative metabolic profiling, heterologous expression, in vitro reconstitution and genomisotopic approaches. The strong interplay of classical natural product chemistry with modern microbial genetics and bioinformatics will help to overcome supply and sustainability issues from the past and to promote bioactive substances from marine Streptomyces to a well-recognised alternative for future drug discovery programs.
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Acknowledgments
The author is grateful to all the authors whose papers have been used for this review and to Ms. Sumantha Alagarsamy for correcting the manuscript. This work was supported by grants from DST-SERC (SR/S0/AS-57/2004) New Delhi, India.
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Dharmaraj, S. Marine Streptomyces as a novel source of bioactive substances. World J Microbiol Biotechnol 26, 2123–2139 (2010). https://doi.org/10.1007/s11274-010-0415-6
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DOI: https://doi.org/10.1007/s11274-010-0415-6