**1. Introduction**

*Streptomyces* are Gram-positive, filamentous bacteria belonging to the group actinomycetes, a group that encompasses the majority of soil bacterial species. It is estimated that a gram of soil contains 109 CFU (colony-forming units) and out of these 109 CFUs, 107 are Actinobacteria [1]. They are ubiquitous soil bacteria, which are also found in the marine environment such as sediments [2]. Some are symbionts of sponges, for example, or insects like the ant *Acromyrmex octospinosus*, which lives in symbiosis with *Streptomyces* (*Streptomyces* S4)-producing antifungals, which help protect fungi cultivated by phytopathogenic ants [3]. *Streptomyces* have a particular development cycle. This cycle begins with a spore that germinates forming vegetative hyphae very little septate that will be structured in a network, the vegetative mycelium whose role is to explore the environment in search of nutrients. The bacterium will form aerial hyphae compartmentalized during a deficiency in element nutrients; these hyphae will then differentiate into spores, which are the form of resistance and dissemination of this bacterium [4].

The production of many secondary metabolites, including antibiotics, is coupled with morphological differentiation. Indeed, we observe a greater production of secondary metabolites during the transition from vegetative growth to aerial growth [5]. During this change in growth type, partial lysis of the mycelium vegetation takes place to provide the necessary nutrients for the creation of aerial mycelium; this release of nutrients could attract competitors. This synchronization of the cycle of development and production of secondary metabolites could be a way for the bacteria to dispel the invaders to keep these nutrients, or else kill the surrounding bacteria to feed them.

> of secondary metabolites. To be able to obtain secondary metabolites, metabolic pathway reaction methods are conducted using multienzyme complexes or an individual enzyme. Genes that encode the synthetic pathway enzyme in general are within chromosomal DNA mostly arranged in cluster formation. As an example, *Streptomycetes griseus* and *Streptomyces glaucescens* chromosomal DNA contain 30 or more str/sts and blu genes that participate in

> **Figure 1.** (a) Phases of bacterial growth and metabolite production. Overall, the major metabolites can be produced at the late interval phase and center of exponential phase, since the minor metabolites can be produced at the end of the stationary phase and during the constant phase. (b) Various pathways responsible for the assembly of secondary metabolites.

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There are many varieties of known secondary metabolites synthesized by six pathways of different biosynthesis (**Figure 1b**): the peptide pathway, the polyketide synthase (PKS) pathway, the nonribosomal polypeptide synthase (NRPS) pathway, the hybrid (nonribosmial polyketide synthetic) pathway, the shikimate pathway, the β-lactam synthetic pathway, and the carbohydrate pathway. The pathway peptide concerns a part of the protein secondary

streptomycin biosynthesis.

The secondary metabolite-producing microorganisms synthesize these bioactive and complex molecules at the lag phase and stationary phase of their growth (**Figure 1a**). However, regarding actinomycetes and *Streptomyces* especially, secondary metabolites can be produced at exponential, stationary, and death phases [6, 7]. It appears in times of environmental issues that nutrient depletion-limiting growth conditions allow formation of secondary metabolites. These are mostly found in fungi, plants, soil, and marine environments and organisms. Its has also been found that different organisms can produce metabolites that have various biological abilities, which include metal transporting agents, sex hormones, toxins, pigments, pesticides, immunosuppressants, anticancer agents, antibacterial agents, immunomodulating agents, antagonists, and receptor antagonists. The intermediate or finished products of primary metabolic pathways are obtained from their own systematic pathways for the synthesis

derivatives to high molecular weight proteides, and macrolactones from simple eight membered lactones to different condensed macrolactones. Berdy (1974) introduced the first classification scheme for antibiotics referring to the chemical structure. On the basis of Berdy's scheme, (1996) recognized that both low and high molecular weight compounds

**Keywords:** antibiotics, PKS, NRPS, *Streptomyces*, secondary metabolites, antibacterial

*Streptomyces* are Gram-positive, filamentous bacteria belonging to the group actinomycetes, a group that encompasses the majority of soil bacterial species. It is estimated that a gram of soil contains 109 CFU (colony-forming units) and out of these 109 CFUs, 107 are Actinobacteria [1]. They are ubiquitous soil bacteria, which are also found in the marine environment such as sediments [2]. Some are symbionts of sponges, for example, or insects like the ant *Acromyrmex octospinosus*, which lives in symbiosis with *Streptomyces* (*Streptomyces* S4)-producing antifungals, which help protect fungi cultivated by phytopathogenic ants [3]. *Streptomyces* have a particular development cycle. This cycle begins with a spore that germinates forming vegetative hyphae very little septate that will be structured in a network, the vegetative mycelium whose role is to explore the environment in search of nutrients. The bacterium will form aerial hyphae compartmentalized during a deficiency in element nutrients; these hyphae will then differentiate into spores, which are the form of resistance

The production of many secondary metabolites, including antibiotics, is coupled with morphological differentiation. Indeed, we observe a greater production of secondary metabolites during the transition from vegetative growth to aerial growth [5]. During this change in growth type, partial lysis of the mycelium vegetation takes place to provide the necessary nutrients for the creation of aerial mycelium; this release of nutrients could attract competitors. This synchronization of the cycle of development and production of secondary metabolites could be a way for the bacteria to dispel the invaders to keep these nutrients, or else kill

The secondary metabolite-producing microorganisms synthesize these bioactive and complex molecules at the lag phase and stationary phase of their growth (**Figure 1a**). However, regarding actinomycetes and *Streptomyces* especially, secondary metabolites can be produced at exponential, stationary, and death phases [6, 7]. It appears in times of environmental issues that nutrient depletion-limiting growth conditions allow formation of secondary metabolites. These are mostly found in fungi, plants, soil, and marine environments and organisms. Its has also been found that different organisms can produce metabolites that have various biological abilities, which include metal transporting agents, sex hormones, toxins, pigments, pesticides, immunosuppressants, anticancer agents, antibacterial agents, immunomodulating agents, antagonists, and receptor antagonists. The intermediate or finished products of primary metabolic pathways are obtained from their own systematic pathways for the synthesis

from 63 different chemical classes are produced by streptomycetes.

**1. Introduction**

100 Basic Biology and Applications of Actinobacteria

and dissemination of this bacterium [4].

the surrounding bacteria to feed them.

**Figure 1.** (a) Phases of bacterial growth and metabolite production. Overall, the major metabolites can be produced at the late interval phase and center of exponential phase, since the minor metabolites can be produced at the end of the stationary phase and during the constant phase. (b) Various pathways responsible for the assembly of secondary metabolites.

of secondary metabolites. To be able to obtain secondary metabolites, metabolic pathway reaction methods are conducted using multienzyme complexes or an individual enzyme. Genes that encode the synthetic pathway enzyme in general are within chromosomal DNA mostly arranged in cluster formation. As an example, *Streptomycetes griseus* and *Streptomyces glaucescens* chromosomal DNA contain 30 or more str/sts and blu genes that participate in streptomycin biosynthesis.

There are many varieties of known secondary metabolites synthesized by six pathways of different biosynthesis (**Figure 1b**): the peptide pathway, the polyketide synthase (PKS) pathway, the nonribosomal polypeptide synthase (NRPS) pathway, the hybrid (nonribosmial polyketide synthetic) pathway, the shikimate pathway, the β-lactam synthetic pathway, and the carbohydrate pathway. The pathway peptide concerns a part of the protein secondary metabolites: they are synthesized by simple translation of mRNAs into peptides by ribosomes. NRPSs are enzymes capable of condensing amino acids to form peptides without going through the ribosomal synthesis pathway. PKSs are enzymes capable of synthesizing a particular family of secondary metabolites: polyketides. The enzymes necessary for the synthesis of these polyketides are homologous to fatty acid synthase (FAS), which is responsible for the synthesis of fatty acid chains. Like the FASs these enzymes can couple precursors to form a chain. This chain will then undergo eight post-PKS changes before becoming active. Regarding the carbohydrate (known scientifically as oligosaccharide) route, it is based on the use of enzymes capable of coupling different sugars to form a carbohydrate precursor; this chain will then undergo modifications that will make the precursor active [8].

isolated are recognized as producers of antibiotics [25]. Actinomycetes synthesize two-thirds of the microbial antibiotics of which about 80% are isolated from the genus *Streptomyces*. Even if other secondary metabolites are included, the actinomycetes remain the largest suppliers with about 60% (*Streptomyces* always have the biggest part with 80%). More than 60 substances with antibiotic activity produced by *Streptomyces* species are used not only in the world of veterinary and human medicine, but also in the field of agriculture and industry. The capacity of the members of the genus *Streptomyces* [27, 28] to produce commercially significant compounds, especially antibiotics, remains unsurpassed, possibly because of the extra-large DNA complement of these bacteria [17]. Antibiotics that come from Actinobacteria are grouped together so that they belong in their major structural classes. Examples of these are ansamycins (ritamycin), macrolides (erythromycin, azithromycin, and clarithromycin), aminoglycosides (streptomycin, kanamycin, tobramycin, gentamicin, and neomycin), tetracyclines, anthracyclines (doxorubicin), and β-lactam (penicillin, cephalosporin, carbapenems, and monobactams). Streptomycin and its varying species strains have been responsible for the production of most antibiotics and it appears that these organisms produce antibiotics to kill off potential competitors [29]. Streptomycin was one of the first antibiotics found. It is produced by *S. griseus* [30]. Today, various *Streptomyces* species are responsible for approximately 75% of both medical and commercial antibiotics and work very well in these areas. Due to the need for new antibiotics, studies have steered towards the isolation of streptomycetes and the careful screening of different habitats in which they are used. It has also been found through research that different conditions such as nutrients, culturing, and other factors may affect how *Streptomyces* develop to form antibiotics. With this in mind the medium constitution along with metabolic capacity of any organism production can affect antibiotic biosynthesis. Research into actinomycetes has found that they are capable of producing more one antibiotic (e.g. *S. griseus and S. hygroscopicus*) and also the same antibiotic can produce various species of Actinobacteria (e.g. streptothricin and actinomycin). Therefore, an antibiotic may be exactly the same with the same chemical composition and antibiotic spectrum as a produced Actinobacterium (**Table 1**). The table gives a list of antibiotics produced by variations of Actinobacteria and how the antimicrobial application has had a profound impact on the medical world where

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previously cancers, tumors, and even malaria could not be treated.

Research has reported that there are a great variety of enzymes that can be applied to biomicrobial fields and biotechnological industries from different genera of actinomycetes. Using the information available from genome and protein sequencing data, actinomycetes are constantly screened and used for producing amylases, xylanases, proteases, chitinases, cellulases, and other enzymes. Industrial applications, for example, the pronase of *S. griseus* and the kerase of *Streptomyces fradiae*, are used for the commercial production of biotechnology products such as hydrolysate proteins from different protein sources [31]. The proteases of *Streptomyces* have the advantage of easy elimination of the mycelium by filtration or simple centrifugation [32]. Similarly, Actinobacteria have been revealed to be an excellent resource for L-asparginase, which is produced by a range of Actinobacteria, mainly those from soils such as *S. griseus*,

*Streptomyces karnatakensis, Streptomyces albidoflavus*, and *Nocardia* spp. [33, 34] (**Table 2**).

**2.2. Production of enzymes**
