Understanding microbial pathogens: current knowledge and educational ideas on antimicrobial research (Enrique Torres-Hergueta and A. Méndez-Vilas, Eds.) Antimicrobial agents produced by Streptomyces Naeima M.H. Yousef* Department of Botany & Microbiology, Faculty of Science, Assiut University, 71516 Assiut, Egypt * Corresponding author: email: [email protected] Streptomyces is a genus of Gram-positive, aerobic, filamentous and non-acid-fast actinobacteria that belongs to the family streptomycetaceae and represents the largest genus of actinobacteria. It is common in various environments; soil, composts, water (rivers and marine) and plants. The genus comprises more than 600 species with validated names. The most interesting features of Streptomyces is its ability to produce bioactive secondary metabolites, such as antifungal, antibacterial, antiviral, antitumor, anti-hypertensives, immunosuppressant, and several others. The genus produces over two-thirds of the clinically useful antibiotics of natural origin related to aminoglycosides, β-lactams, macrolides and tetracyclines. The production of most antibiotics is species specific, and the species produce them to compete with other microorganisms in the same habitats. In addition, these antibiotics protect the plant against microbial pathogens. The objectives of the current review are to shed light on the genus Streptomyces; diversity, general features and the role of this genus in production of highly valuable antimicrobial agents that commonly used in treatment of some virulent pathogens. Keywords: Streptomyces; Soil; Antibiotics; Plants; Antimicrobial agents 1. Streptomyces The name Streptomyces is derived from the Greek strepto- meaning twisted, alluding to this genus' chain- like spore production; myces means filament. The genus Streptomyces belongs to the family Streptomycetaceae and it represents the largest genus of Actinomycetes [1]. Streptomyces is a Gram-positive, aerobic, non-acid-alcohol-fast actinobacteria and has genomes with high GC-content; the mol% G+C content of the DNA lies between 69 and 78 [2,3]. Species are widely distributed and abundant in soil, including composts, plants, marine water and rivers. A few species are phytopathogens; a few others are pathogenic for humans and animals. It is characterized by an extensively branched substrate mycelium and aerial hyphae, 0.5–2.0 mm diameter, rarely fragmented or have no septation [4]. At maturity, the aerial mycelium forms chains of three to several spores (Figure 1). Some members have sporangia-, pycnidial-, sclerotia-, and synnemata-like structures [5]. The spores are nonmotile, its surface may be hairy, rugose, smooth, spiny or warty [6]. Frequently, colonies initially have a smooth surface but later develop a weft of aerial mycelium that may appear floccose, granular, powdery, or velvety. Colonies are discrete and lichenoid, leathery, or butyrous. Streptomyces produce a wide range of pigments responsible for the color of the vegetative and aerial mycelia. Additionally, colored diffusible pigments may be generated [3]. Fig. 1 Cross section of Streptomyces colony. The optimal growth temperature for most species ranged between 25–35οC. However, some species can grow at temperatures within the psychrophilic and thermophilic range. The optimum pH range for growth varied between 6.5 and 8.0. The genus can produce earthy odor that results from production of volatile metabolites geosmin (literally ‘earth smell) which gives the soil its characteristic smell, and provides an indication of just how widespread these bacteria are in the soil [7]. Upon its first characterization, it was noted that S. antibioticus produces a distinct soil odor. Streptomyces are not just free-living soil bacteria, but also form symbioses with other organisms, most notably plants and invertebrates [8]. They used Streptomyces antibiotics producer to protect themselves against infection, on the other 55 Understanding microbial pathogens: current knowledge and educational ideas on antimicrobial research (Enrique Torres-Hergueta and A. Méndez-Vilas, Eds.) hand, the plant can produce exudates which allows the development of Streptomyces in the symbiosis between Streptomyces and plants. Their species may be pathogenic for humans (such as S. somaliensis and S. sudanensiscausing mycetoma), animals or plants (such as S. caviscabies, S. acidiscabies, S. turgidiscabies and S. scabies) [9]. The nutrition of Streptomyces is chemoorganotrophic with an oxidative type of metabolism. Streptomyces is catalase positive, usually degrade polymeric substrates such as casein, gelatin, hypoxanthine, and starch in addition to adenine and L-tyrosine and reduce nitrates to nitrites. Peptidoglycan is the main component of cell wall, contains major quantities of LL-diaminopimelic acid, sometimes, low amounts of meso-diaminopimelic acid are present. The lipid profile contains major amounts of saturated, iso- and anteiso-fatty acids but lacks mycolic acids. In addition, they typically possess either hexa- or octa-hydrogenated menaquinones with nine isoprene units as the predominant isoprenolog, but menaquinones with eight and ten isoprene units are also found. A complex polar lipid pattern normally contains diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylinositol mannosides [10]. All Streptomyces strains studied contain a large genome, typically of linear topology. The chromosomes of sequenced Streptomyces range in size from 6,283,062 bp for S. cattleya to 11,936,683 bp predicted to code for 10,023 genes in S. bingchenggensis. The S. coelicolor A3(2) genome was originally considered to be circular and representing the model Streptomycetes [11]. In addition Streptomyces can contain small, covalently closed circular (ccc) high copy- number plasmids, larger ccc low copy-number plasmids, ccc plasmids that arise by reversible site-specific recombination from the chromosome, and linear plasmids that share features of the chromosome: a centrally located origin of replication and terminal inverted repeats with bound terminal proteins to prime end patching. A property common to may be all is their self transmissibility and ability to mobilize chromosomal DNA, making them supremely important in promoting genetic exchange and Streptomyces evolution [3]. Streptomyces considered as a promising source of wide range of important enzymes, some of which are produced on an industrial scale. They could produce amylase, cellulase, protease, tyrosinase, chitinase, lipase, catalase and phosphatase [12]. They have the ability to degrade a wide range of hydrocarbons, pesticides, aliphatic and aromatic compounds [13]. They have an important ecological role in the turnover of organic material in the soil. Streptomyces act as plant growth promoting rhizobacteria (PGPR) such as S. atrovirens which produce plant growth hormone; indol acetic acid (IAA) [14]. As well as, they are enormously important to human medicine, agriculture and food production [8]. The most interesting property of Streptomyces is the ability to produce bioactive secondary metabolites, such as antibacterial, antifungal, antiviral, antitumor, antiparasitic anti-hypertensives, and immunosuppressant compounds [15]. They produce over two-thirds of the clinically useful antibiotics of natural origin (e.g., streptomycin, neomycin and chloramphenicol, etc.) [16]. The production of most antibiotics is species specific, many strains are able to produce one or more antibiotic compounds to compete with other microorganisms in the environment and protect the plant against different pathogens. Streptomyces is one of the most predominantly sources of antibiotics used in many pharmaceutical and biotechnological applications. Almost all of the bioactive compounds produced by Streptomyces are initiated during the time coinciding with the aerial hyphal formation from the substrate mycelium [5]. Streptomyces carry resistance to their own antibiotics to avoid suicide and, under selective pressure, these resistance genes can spread to other soil bacteria and to pathogenic bacteria via horizontal gene transfer [17]. The history of antibiotics, which inhibit bacterial growth, started at 1942 with the discovery of streptothricin from Streptomyces, followed by the discovery of streptomycin, after that, the scientists intensified the search for other antibiotics from the genus. The antibiotics produced by Streptomyces were classified according to chemical structure into 6 categories: aminoglycosides, beta-lactams (β-lactams), chloramphenicol, lipopeptide, macrolides and tetracyclines, some of which aminoglycosides and β-Lactams act as bactericidal agents and others (tetracyclines, chloramphenicol and macrolides) as bacteriostatic agents. 2. Aminoglycosides Aminoglycosides are class of antibiotics (contain aminosugar substructures) that possess cyclohexyl rings substituted with amine groups and linked together by glycosidic bonds. Several Streptomyces species could produce aminoglycosides antibiotics such as streptomycin (produced by S. griseus), neomycin (S. fradiae) and kanamycin (S. kanamyceticus), gentamycin (actinobacterium Micromonospora purpurea) and tobramycin (S. tenebrarius). The most common and highly important of these antibiotics are streptomycin and neomycin. They have extensive application in the treatment of numerous infectious diseases. 2.1 Streptomycin The aminoglycoside antibiotic streptomycin was first isolated in 1943, by Schatz and Waksman (Torok et al. 2009). Streptomycin was also