Streptomyces aureofaciens

Nocardia rugosa Propionibacterium arabinosum Propionibacteriumfreudenreichii Propionibacterium pentosaceum Propionibacterium peterssoni Propionibacterium shermanii Propionibacterium technicum Propionibacterium vannielli Protaminobacter ruber Pseudomonas denitrificans Bhi bium meliloti Bhodopseudomonas capsulata Bhodopseudomonas spheroides Strigomonas oncopelti Streptomyces aureofaciens Streptomyces griseus Streptomyces olivaceus... 

Streptomyces aureofaciens naturally produces chlortetracydine. This has the structure... 

From fermentation solutions of a Streptomyces aureofaciens mutant. Reference(s) ... 

The microorganism is again P. chrysogenum. A manufacturer may use the same mutant strain to make both products or may have different mutants for the two penicillins. Parallel situations of a single organism producing more than one natural product occur with other types of antibiotics, for example strains of Streptomyces aureofaciens are used for both chlortetracycline and demethylchlortetracycline fermentations. 

Weng M, O Pfeifer, S Kraus, F Lingens, K-H van Pee (1991) Purification, characterization and comparison of two non-heme bromoperoxidases from Streptomyces aureofaciens. J Gen Microbiol 137 2539-2546. 

Chlortetracycline hydrochloride (CTC-HCL) is the hydrochloride salt of an antibiotic substance produced by the growth of Streptomyces aureofaciens (Fam. Streptomycetaceae). 

A medium (containing corn steep liquor calcium carbonate sucrose ammonium, ferrous, manganese, and zinc sulfates and ammonium, cobalt, and magnesium chlorides) is sterilized and diluted with water to the desired concentration. It is inoculated with Streptomyces aureofaciens, kept at 27°C, and aerated and agitated for 60 hours, with lard oil added to control foaming (66). 

The mash from the Streptomyces aureofaciens fermentation broth is acidified and filtered. The filtrate is adjusted to the desired pH, usually 7-8.5, and various flocculating or chelating agents may be added (e.g., vinyl acetate-maleic anhydride copolymer, sodium EDTA, ammonium oxalate, Arquad). The precipitate is (1) stirred with filter aid, filtered, stirred with HC1, refiltered, mixed with 2-ethoxyethanol, filtered, washed, and the filtrates are combined, acidified with HC1, NaCl is added, and the crystals are collected, washed with 2-ethoxyethanol, water, and ethanol, and dried (67), or (2) extracted into methyl isobutyl ketone, the extracts are combined, filtered, and acidified with HC1, and the crystals are collected and washed with water, 2-ethoxyethanol, and isopropanol, and vacuum-dried. If the crystals are greenish, they are treated with sodium hydrosulfite at pH 1.8, filtered, washed, and dried as in (1) above (68). 

Tetracyclines are a group of antibiotics derived from bacteria. Chlortet-racycline was isolated from Streptomyces aureofaciens and oxytetracycline from Streptomyces rimosus. Tetracychnes act by binding to receptors on the bacterial ribosome and inhibit bacterial protein synthesis. 

The first antibiotic of the tetracycline series, chlorotetracycUne, which was isolated from a culture liquid of Streptomyces aureofaciens, was introduced into medical practice in 1948. Conseqnently, there were another six dmgs of the tetracycline series that were introdnced into medical practice between 1950 and 1972. Oxytetracycline is isolated from Streptomyces rimosus tetracycline (semisynthetic), demeclocycline is isolated from the mutant type of S. aureofaciens methacycUne (semisynthetic), doxycycUne (semisynthetic), and minocycline (semisynthetic). Methods of synthesis of the tetracycline series antibiotics have been sng-gested however, they are purely of an academic interest and do not have any practical valne. 

Streptomyces aureofaciens, then oxytetracycline was derived from Streptomyces rimosus and then tetracycline was obtained by catalytic dehalogenation of chlortetracycline. They are classified as in table 9.2.1. 

Although no new halogen-containing tetracyclines have been reported since the first survey (1), the gene responsible for the chlorination of tetracycline in Streptomyces aureofaciens (Fig. 3.24) has been cloned and the sequence of nucleotides determined (1651). The gene product is a 452 amino acid chlorination enzyme. 

Fig. 3.24 Streptomyces aureofaciens, the microorganism that produces the tetracyclines (Photo T. Rezanka)...

Laatsch H, Pudleiner H, Pelizaeus B, van Pee K-H (1994) Enzymatische Bromierung von Pseudilinen und verwandten Heteroarylphenolen mit der Chlorperoxidase aus Streptomyces aureofaciens Tii 24. Liebigs Ann Chem 65... 

Pfeifer O, Pelletier I, Altenbuchner J, van Pee K-H (1992) Molecular Cloning and Sequencing of a Non-Haem Bromoperoxidase Gene from Streptomyces aureofaciens ATCC 10762. J Gen Microbiol 138 1123... 

Hecht HJ, Sobek H, Haag T, Pfeifer O, van Pee K-H (1994) The Metal-Ion-Free Oxidore-ductase from Streptomyces aureofaciens has an a/P Hydrolase Fold. Struct Biol 1 532... 

Kren V, Kawulokova L, Sedmera P, Polasek M, Lindhorst TK, van Pee K-H (1997) Biotransformation of Ergot Alkaloids by Haloperoxidase from Streptomyces aureofaciens. Stereoselective Acetoxylation and Propionoxylation. Liebigs Ann/Recueil 2379... 

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by cultures of Streptomyces species. Chlortetracycline isolated from Streptomyces aureofaciens was the first of the group to be discovered, closely followed by oxytetracycline from cultures of S. rimosus. Tetracycline was found as a minor antibiotic in S. aureofaciens, but may be produced in quantity by utilizing a mutant strain blocked in the chlorination step b (Figure 3.54). Similarly, the early C-6 methylation step (included in a) can also be blocked, and such mutants accumulate 6-demethyltetracyclines, e.g. demeclocycline (demethylchlorotetracycline). These reactions can also be inhibited in the normal strain of S. aureofaciens by supplying cultures with either aminopterin (which inhibits C-6 methylation) or mercaptothiazole (which inhibits C-7 chlorination). Oxytetracycline from S. rimosus lacks... 

During the course of experiments for the elucidation of the structure of the two earlier discovered compounds chlortetracycline (CTC) and oxytetracycline (OTC) it was found that hydrogenation of chlortetracycline resulted in halogenolysis and the product tetracycline (TC) retained the useful activity spectrum of the first two members of the family. TC appears to represent the first clinically successful antibiotic produced by shere chemical manipulation of preexisting antibiotic. TC was found to be present in fermentations of both cultures streptomyces aureofaciens and streptomyces rimosus as well as in streptomyces viridofaciens (1). 

Tetracycline is usually prepared by the catalytic dechlorination of chlortetracycline as described in US Patents 2,699,054 and 3,005,023, or obtained directly by fermentation of Streptomyces aureofaciens or Streptomyces viridifaciens according to US Patents 2,712,517, 2,734,018, 2,886,595 and 3,019,173. The purification of tetracycline produced by either route is described in US Patent 3,301,899. 

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