The Marine Actinomycetes: History
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The phylum Actinomycetota (Actinobacteria) is one of the main branches or lineages of bacteria gifted with antibiotic producing capabilities. Marine actinomycetes are emerging as a promising candidate for bioactive metabolites, encompassing very complex compounds with pharmacological activities. Genomic insights of marine actinomycetes further revealed their immense biosynthetic potential. Cultivation and fermentation of marine actinomycetes requires expertise on their physiological characteristics and optimum growth conditions or requirements. 

  • Marine actinomycetes
  • Actinomycetes
  • Bioactive compounds

1. Actinomycetes: A Teeming Wealth of Chemical and Biological Warfare

The phylum Actinomycetota (Actinobacteria) is one of the main branches or lineages of bacteria (http://www.bacterio.net/-classifphyla.html#actinobacteria, accessed on 1 September 2021). This group of bacteria has different mechanisms of action, which make them a major natural source of antibiotics. Hereinafter, the term actinomycetes refers to members of the phylum Actinomycetota (Actinobacteria). Actinobacteria, sometimes called actinomycetes, are Gram-positive bacteria that can be unicellular (e.g., Arthrobacter spp.) or multicellular (e.g., Streptomyces spp.) with non-spore- and spore-forming abilities. They contain sufficient guanine and cytosine contents in their genome and are predominantly aerobic with a few anaerobic and facultative exceptions, but are phylogenetically diverse exhibiting filamentous characteristics [1]. Although actinomycetes share a morphological resemblance to both fungi and other bacteria, their high GC content separates them as a distinct bacterial group. Actinomycetes, including both symbionts (e.g., Frankia spp.) and pathogens (e.g., Corynebacterium diphtheriae) are free-living, saprophytic and ubiquitous in terrestrial and aquatic environments. They are the most biotechnological and economical microorganisms that live under the most diverse conditions [2]. In addition, actinomycete is one of the major contributors to the production of geosmin and 2-methylisoborneol (2-MIB). These secondary compounds are tertiary alcohols, widely known to cause earthy and musty odors [3]. Actinomycetes appear to be very competitive under adverse environmental conditions due to certain properties they possess. First, they can produce a wide range of spores in a very short period of vegetative growth. Second, actinomycetes are versatile in terms of acquiring nutrition. Their growth is viable whether there is the sufficient availability of the minimum amount of nutrients or no nutrients. Third, having the ability to grow mycelium coordinates the colonization of nutrients away from the growth center. Finally, actinomycetes are able to synthesize compounds that prevent them from undergoing microbial degradation as well as the production of secondary metabolites, which are used to their advantage against other microorganisms [4]. It is worth stating that the production of secondary metabolites is strictly dependent on actinomycetes’ morphological and physiological cell differentiation [5]. Actinomycetes acquire resistance to their own antibiotics due to their resistant genes in order to prevent them committing suicide. However, under selective pressure such as the persistent exposure to antibiotics, these resistant genes are transferred, in a process called horizontal gene transfer, to other bacteria, including groups of pathogens [6][7].
Although actinomycetes are free-living organisms, some are opportunistic pathogens [1]. As well as their importance as a significant contributor to soil ecology in terms of degradation and the renewal of complex polymers such as chitin, cellulose, keratin and lignin [8], Actinobacteria are widely responsible for a growing number of antibiotic productions. It has been reported that around 500,000 natural compounds are derived from biological sources, and 70,000 of these natural compounds are of microbial origin, of which 29% are obtained from actinomycetes [9]. Actinomycetes are certainly the most lucrative and inexhaustible synthesizers of secondary metabolites with different ranges of biological activities among distinct microorganisms. Since the discovery of penicillin in 1928 by Alexander Fleming, about 80% of clinical antibiotics have come from the genus Streptomyces [10], with more than 500 of its species believed to be responsible for all of the bioactive metabolites discovered [11]. This genus is widely recognized for its extreme metabolic versatility. Actinobacteria are widely valued as a myriad resource in drug development with compounds that have cytotoxic/antitumor activity 39%, antimicrobial 31%, anti-HIV 1%, antimalarial 6%, antioxidant 2%, inhibitors 4%, antiinflammatory 5%, and other activity 10% [12]. Most of the active metabolites, including well-known drugs (erythromycin, streptomycin, tetracycline, antifungal compound nystatin, anthelmintic, avermectin, immunosuppressant rapamycin, and anticancer agents bleomycin and doxorubicin) have been shown to have distinctive structures and greater potency against infectious diseases [8]. The ability of actinomycete strains to produce a variety of antibiotics varies widely since some produce a single antibiotic, while others produce a wide range of antibiotics. With the development of high-end technologies, the genomes of actinomycetes are able to be sequenced, which has, relatively, unraveled their huge genomes and encoded a number of intriguing metabolites. Interestingly, each strain of actinomycete is genetically capable of producing 10–20 bioactive compounds [13]. Actinomycetes have a very differentiated and complex life cycle. They develop as mycelium and reproduce by sporulation [1]. Sometimes the growth or reproduction of actinomycetes is slow, so they are called slow growth. Most actinobacteria spend their life cycle as semi-dormant spores as a survival mechanism in the response to stress [1]. These spores are mostly resistant to desiccation, heating, some antibiotics and chemicals [9]. Under appropriate conditions, these spores are revived or reactivated, and their life cycle continues [1].

2. Marine Actinomycetes: A Potential Frontier of Bioactive Compounds

Marine actinomycetes are emerging as a promising candidate for bioactive metabolites, encompassing very complex compounds with pharmacological activities [14]. There is significant potential for the availability of bioactive compounds in marine actinomycetes, which are characterized as antimalarial, antibacterial, antifungal, anticancer, antitumor, antiinflammatory, cytotoxic and antimicrobial agents [15]. In addition to the synthesis of chemically active agents, marine actinomycetes promote the mineralization and degradation of organic matter and pollutants. They play a determining role in the biogeochemical processes of the oceans, thus maintaining the integrity of a particular marine environment [16]. Recent advances in marine drug research have mainly focused on marine actinomycetes, since two-thirds of polyketide drugs are obtained from this unique taxon [17]. Marine actinomycetes are valuable prokaryotes of economic and biotechnological importance. It has been reported previously that less than 1% of actinomycetes have been documented, in particular due to the dynamics and complexity of the microbial population [18]. Actinomycetes are widely distributed within ocean boundaries with highly developed morphological and cultural characteristics, so the majority remain untapped or elusive [19][20]. They are isolated from less extreme to extreme marine habitats, including sediment and seawater. Marine actinomycetes represent a tenth of all marine bacteria [2]. The extent of the diversity of marine actinomycetes is enormous due to the diversity of marine habitats. Several studies clearly documented the presence of marine actinobacteria by discovering Rhodococcus marinonascene, the first species of marine actinobacteria described [21]. However, it was widely believed that marine actinomycetes derived primarily from the dominant spores originated from the terrestrial ecosystem [22]. A number of studies have shown that strains of actinomycetes have developed certain characteristics of marine adaptation in order to survive [23], while others are metabolically active in the marine environment [24]. Compelling evidence regarding the widespread and persistent occurrence of native actinomycetes was first reported by Mincer et al. [25]. These findings subsequently paved the way for the discovery of a new genus of obligate marine actinobacteria Salinispora (also known as Salinospora) [26]. This new discovery clearly proves that actinomycetes are indigenous to the marine environment and are able to create unique bioactive compounds of interest to pharmaceutical researchers. Culture-independent studies have further proven that indigenous marine actinomycetes belong to the genera Streptomyces, Dietzia, Solwaraspora, Williamsia, Marinispora, Verrucosispora, Aeromicrobium, Salinispora, Salinibacterium and  Rhodococcus [20][27]. An interesting recent review by Voser et al. [28] on “How different are marine microbial natural products compared to their terrestrial counterparts?” did an excellent job of summarizing 55,817 compounds reported from marine and terrestrial microorganisms and showed that 76.7% of the compounds isolated from marine microorganisms are closely related to compounds isolated from terrestrial microorganisms. They suggest that increasing incubation times and using specific culture-based methods that mimic marine environments is paramount for targeting unique marine actinobacteria compounds [28]. Having a holistic perspective on a variety of these diverse culture-based methods can help researchers design isolation methods accordingly, as the cost of marine research has been estimated to be an order of magnitude higher than equivalent land-based studies [29].

3. Genomic Insight of Marine Actinomycetes

Metagenomic studies have given an insight into the evolutionary history, diversity and number of unculturable Actinobacteria, including those from marine habitats [30]. With the development and advancement of genome sequencing, an immense amount of DNA sequence data are available from public databases. The advent of the genomic era has revolutionized the approaches in drug discovery [31]. Genome mining is a powerful tool that has the ability to showcase the entire biosynthetic potential of a microbe [32][33]. For instance, genome mining approaches were employed to unveil the huge number of biosynthetic gene clusters for secondary metabolites from marine-derived actinomycetes. A study by Undabarrena et al. [34] not only showed that Streptomyces sp. H-KF8 isolated from marine sediments has 26 biosynthetic gene clusters for secondary metabolites, but also that it has the ability to tolerate a wide range of heavy metals. Another study unveiled 176 distinct biosynthetic gene clusters among three closely related species of the genus Salinispora isolated from various marine habitats of which 24 of the BGCs had a connection to their products [35]. Additionally, Xu et al. [36] analyzed 87 marine Streptomyces genomes isolated from marine sediments and invertebrates and revealed their number of secondary metabolite biosynthetic gene clusters, ranging from 16 to 84. Securing close and high-quality genomes remains vital to achieve accurate genome mining and in silico identification outputs of secondary metabolite biosynthetic gene clusters [37]. As more marine organisms are sequenced, the functions and applications of genome mining become more common in retrieving unique marine compounds [38]. However, genome mining for drug discovery from marine natural products is often challenged by predictions of chemical structures, novel classes and the activation of silent gene clusters [38]. The introduction of high throughput molecular techniques such as metagenomics is deemed appropriate for microbiota investigations that culture-based techniques have failed to investigate. With a richer knowledge and deeper insight into the functional characteristics of actinomycetes based on culture-independent studies, improved techniques have been developed to cultivate and recover previously uncultivable actinomycetes [39][40][41][42]. Indeed, the whole genome studies have revealed the immense potential of marine actinomycetes.

4. Cultivation Techniques of Marine Actinomycetes

Marine actinomycetes have special growing conditions that must be met for proper growth in the laboratory. A higher percentage of microbial cells in unexplored or underexplored habitats remain viable but uncultivable (VBNC) [37], as few microbial colonies can be isolated by conventional approaches in the laboratory. The isolation of actinomycetes from the marine environment requires expertise on the physiological characteristics of actinomycetes, and the taxonomies and isolation parameters such as the components and concentration of the medium, culture temperature, pH and incubation time [43]. Understanding these factors provides a higher success rate when it comes to isolating actinomycetes. To successfully grow marine actinomycetes under standard laboratory conditions, selective isolation approaches such as selective isolation media formulated with the preferred nutritional requirements of marine actinomycetes and the use of pretreatment to inhibit the growth of non-actinomycetes are essential. Studies have shown that nutrient-poor environments favor the isolation of rare marine actinomycetes over nutrient-rich environments [9]. Halophilic actinomycetes grow very slowly and, therefore, the isolation plates should have a lower substrate concentration and be thicker; consequently, they have a longer incubation period at appropriate temperatures [44]. In addition, the media must mimic the usual conditions of the microbe. With the abundance of sodium in the ocean, it is an essential prerequisite to add sodium chloride (NaCl) for the growth of most marine organisms. Thus, a well-designed growth medium should have osmotic values similar to those of seawater, which allows the efficient growth of marine actinomycetes [26][45]. This means that a growth medium should contain natural sea water, artificial sea water or deionized/distilled water with the addition of different concentrations of sodium chloride [9]. Moreover, different pretreatment methods should be used such as heat, physics, mechanics, the addition of chemicals or antibiotics, centrifugation, freezing, ultrasonic waves and radiation to remove or suppress the growth of non-actinomycetes (fast growing bacteria and fungi) [9][46]. To cultivate various actinomycetes, about three to five media with different ingredients and concentrations are used [47][48]. These media are able to restrict the growth of other microbes without harming the propagules of actinobacteria [43].

5. Fermentation and Extraction of Bioactive Compounds from Actinomycetes

Actinomycetes are known to produce pigments of orange, yellow, black or blue, greenish brown, pink, red and brown, depending on the type of strain grown, the isolation medium used and the age of the culture [1]. Actinomycetes also produce bioactive molecules in the form of secondary metabolites. The essence of the bioactive compounds generated by actinomycetes strongly depends on the species, strain and culture conditions. The production and secretion of antimicrobial agents do not have fixed yields but can be quantified or suppressed under different culture conditions [49][50]. Studies have shown that to produce the highest antimicrobial metabolites, the pH, incubation time, cell density, type and concentration of carbon sources (maltose, starch, glycerol and glucose) and nitrogen sources (ammonium chloride, soya bean meal, ammonium sulfate, yeast extract, peptone and ammonium nitrate) are essential [51]. Given the limited quantity of bioactive metabolites produced by various microorganisms, including actinomycetes, the applications of fermentation have received merited attention by pharmaceutical entities due to its feasibility for maximizing the production of the most commercial clinical drugs [49]. Fermentation is a biological process; it mostly involves microorganisms that regulate the enzymatic conversion of complex molecules into simple compounds [52]. In drug production, its pathway diverges conventionally into submerged/liquid fermentation (SmF) and solid-state fermentation (SSF) [53][54][55]. These foregoing versions of fermentation are mostly exploited due to their economic and environmental precedence. In spite of that, the outcome of each fermentation technique varies extensively in terms of substrate utilization and productivity [56]. Although SmF has gained wide recognition for its usage at a larger scale in terms of its bioactive secondary metabolites-producing capacity, SSF is emerging and advancing as a promising alternative to SmF [53]. At the research level, the active cultures of actinomycetes based on primary screening are generally cultivated in submerged culture or liquid media for secondary metabolites’ production with the added advantage of a feasible extraction and purification of natural compounds [57]. In order to recover bioactive compounds from the microbial fermentation culture, the extraction process is the first crucial step among a chain of techniques to segregate compounds of interest from raw materials. The extraction of natural compounds employs various extraction techniques, both conventional and modern, but mostly solvent-based extraction [58]. Conventional methods require an organic solvent or water, while modern techniques depend on an elevated temperature and pressure [59]. The Liquid–liquid extraction method or partitioning is commonly utilized for the extraction of secondary metabolites from actinobacteria [60]. Furthermore, the selection of the solvent is essential since extraction is based on the law of similarities and intermiscibility (polarities); both the solvent and solute should have near equivalent polarity values for efficient extraction [58]. The compounds present in the crude extract are rather complex with physical and chemical differences, thus requiring further separation and purification. Chromatography (thin-layer chromatography, column chromatography, and high-performance liquid chromatography) is the frequently used technique to acquire pure natural compounds [60].

This entry is adapted from the peer-reviewed paper 10.3390/microorganisms10071349

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