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Creation of Natural Products: Pathway-Specific Activators

Streptomyces Bacteria: Overview

Belonging to the actinomycete family (Aigle & Corre 2012), streptomyces bacteria have a very peculiar morphology (Jani et al. 2015). Among the key species that comprise the streptomyces bacteria population, Streptomyces coelicolor, Streptomyces ambofaciens (Laureti et al. 2011), Streptomyces lividans, Streptomyces albicans, Streptomyces griseus and Streptomyces plicatosporus (Qi et al. 2014) must be mentioned. The colony shape can be identified as circular (Slama et al. 2015), its elevation being traditionally described as raised (Bhave et al. 2013) and its margins being entire for the most part (Lv et al. 2013). The size of a colony usually ranges from minicompartments (f <0.7 µm) to long compartments (2–3 µm) (Flärdh & Buttner 2009).

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The bacteria are aerobic and gram-positive (Taichi et al. 2013). Streptomyces are characterized by the rather complex structure of aerial hyphae 0.5–2.0 µm long (Bhave et al. 2013), which are capable of forming layers and differentiating into a chain of spores afterward (Duong et al. 2012). As far as the specific properties of the bacteria in question are concerned, their ability to produce bioactive secondary metabolites, including “antifungals, antivirals, antitumorals, anti-hypertensives, immunosuppressants” (Procopio et al. 2912, p. 466) deserves to be mentioned. The specified property is triggered by Sortase activity (Duong et al. 2012). The aerial mass color of Streptomyces incorporates the following color series: “gray (Gy), white (W), red (R), yellow (Y), green (Gn), blue (Bl), and violet (V)” (Tadei, Rodriguez, Márquez-Vilchez & Castelli 2006, p. 222). The substrate mycelium, in its turn, is characterized by the colors of “beige (Bg), black (Bck), blue (Bl), biscuit (Bs), brown (Bw), ivory (Iv), olive (Ol), orange (Or), purple (P), pink (Pk), red (R), red-violet (R-V), tan (T), violet-purple (V-P), yellow (Y), yellow-greenish (Y-Gr)” (Tadei, Rodriguez, Márquez-Vilchez & Castelli 2006, p. 222). Streptomyces produce melanoid pigments and has a spore chain morphology of “Rectus-Flexibilis (RF), spores in straight or flexuous chains, and Spira (S)” (Tadei, Rodriguez, Márquez-Vilchez & Castelli 2006, p. 222).

Streptomyces Coelicolor: Characteristics

Belonging to the genus of Streptomyces, the phylum and class of Actinobacteria, the subclass of Actinobacteridae, the order of Actinomycelates, the suborder of Streptomycineae and the family of Streptomycetaceae (Celler et al. 2012), Streptomyces Coelicolor is Gram-positive (Thompson et al. 2010). It can also be described as filamentous (Speike 2015). The bacteria can be found in the soil, which predetermines outstandingly high rates of adaptability for the aforementioned type of bacteria (Moody, Jones & Eliot 2014). Indeed, Streptomyces Coelicolor may survive on a range of carbon sources, including D-ribose, L-xylitol, D-gluconate, etc. (Chen et al. 2009). The specified characteristics define the earthy smell of the bacteria colonies. On a range of levels, Streptomyces Coelicolor colonies share similarities with fungi (Joshi & Deshmunkh 2011).

Apart from the above-mentioned characteristics, the Streptomyces Coelicolor is easily detected due to its unique color scheme; the colony is usually of a grayish-yellow color (Clark et al. 2013), especially the element of the bacteria known as aerial mycelium (Clark et al. 2013). The melanoid pigment, in its turn, is purely absent in Streptomyces Coelicolor (Clark et al. 2013); more to the point, the aforementioned aerial mycelium does not have spirals in the specified strains of Streptomyces. A Streptomyces Coelicolor colony can also be characterized by its ability to self-assemble into two functional amyloids (Bokhove et al. 2012).

Natural Products

Though Streptomyces Coelicolor genome mining has only been given a major boost comparatively recently, the facts discovered over the past few years are sufficient for considering Streptomyces Coelicolor to be among the most promising research fields to explore. In the light of the fact that novel natural products have been discovered with the help of the genome-based approach, the need to explore the potential of the former and push the envelope by incorporating the newly discovered items into the healthcare realm emerges. The bioactive natural products mentioned by Laureti et al. (2011) are a major foot forward in addressing some of the most topical healthcare issues of the 21st century. The discovery of the natural product-based drugs has obviously reinvented the realm of healthcare as people know it, and the use of cryptic gene encoding as the tool for the application of “macrolides, polyenes, aromatics, and polyethers, which have found therapeutic applications as antibiotics, antitumor agents, immunosuppressants, and cholesterol-lowering drugs” (Laureti et al. 2012, p. 6258) will clearly make a difference in healthcare.

Genome Mining over the Last 10 Years

In the course of the past decade, new tools for genome mining have been discovered, which can be noticed quite easily once the process of the Streptomyces Coelicolor genome mining is taken into account. Indeed, a closer look at the process in question will reveal that the element known as orphan gene has factored in the genome mining procedure, therefore, facilitating a far more expeditious method and creating the premises for retrieving far more fruitful results (Corre & Challis 2007, p. 7). The process of genome mining has clearly been geared towards the natural products retrieval process mentioned above, which the genome analysis of the Streptomyces Coelicolor mentioned above is a graphic example of. To be more specific, the discovery of the so-called “orphan” (Corre & Challis 2007, p. 8) genome clusters has predetermined the creation of the genomisotropic approach as the key strategy in the genome mining process (Corre & Challis 2007).

More to the point, the discovery of new products may ensue the use of genome mining as the basic approach in addressing healthcare and medicine-related issues from the perspective of genetics. As recent data shows, “Many new natural products with potential clinical utility could therefore be discovered” (Aigle & Corre, 2012, p. 362 Aigle & Corre, 2012, p. 362) with the adoption of the genome-based approach in general and the genome clusters strategy in particular due to the “exploitation of the large number of untapped biosynthetic gene clusters” (Aigle & Corre, 2012, p. 362).

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Methods of New Antibiotics Discovery

As it has been stressed above, the use of the aforementioned bacteria allows for the discovery of new types of antibiotics and, therefore, a more efficient treatment of a range of disease, such as the carbapenem-resistant Klebsiella pneumonia (Procopio et al. 2912, p. 469), etc. As a rule, two key types of retrieving antibiotics from Streptomyces Coelicolor are distinguished as the most efficient ones. Though the overexpression of transcriptional activators has its problems as a method for antibiotics production, it is still generally preferred to the inactivation of repressor, as the latter allows for suppressing the natural product-based feedback inhibition (Navone et al. 2014).

Therefore, when it comes to defining the basic methods of antibiotic discovery, the methods such as the activation of the silent polyketide synthase (Laureti et al. 2011) deserves to be mentioned. Favored largely because of the simplicity of the process, it is often compared to fatty acid in terms of the ease and speed of antibiotics retrieval (Masschelein et al. 2015)

Overexpression of Transcriptional Activators

Traditionally preferred over the inactivation of repressor, the specified approach can be deemed as rather efficient in terms of antibiotics retrieval. According to the existing evidence, the method involving overexpression of transcriptional activators is more efficient due to the opportunity to inhibit the negative effect of the repressor, which it allows for (Pillai et al. 2001). Another obvious reason that makes the specified approach superior to that one of inactivating the repressor, the MM2 and MM5 production property must be brought up. Indeed, according to the results of the research concerning the subject matter, the pET151 plasmid “was used to transform E. coli BL21star. LC-MS analyses of culture supernatant organic extracts showed that induction of mmfL overexpression in this strain resulted in the production of MMF2 and MMF5” (Corre et al. 2008, p. 17512).

Inactivation of Repressor

It would be wrong to claim that the inactivation of repressor is not legitimate as a tool for retrieving antibiotics with the help of Streptomyces Coelicolor. The transcriptional repressor GbnR in S. venezuelae (Sidda et al. 2013) allows for suppressing the effects of the gbn gene cluster (Sidda et al. 2013, p. 88). As a result, the production of antibiotic-like chemicals commences (Sidda et al. 2013). The given approach, however, needs to be fully tested yet, as the authors of the study admit it to be comparatively new and in desperate need for detecting the possible issues that may arise in the process (Sidda et al. 2013, p. 89).

Reference List

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