Streptomyces aureofaciens Tetracyclines

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)...

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. 

One year later, the American pharmaceutical company Pfizer discovered a related structure - christened oxytetracycline (Terramycin) - from Streptomyces rimosus. Interestingly, this was found in a soil sample located near their factory in Terre Haute, Indiana. The parent structure - tetracycline - was then obtained by chemical removal of the chlorine atom (an element only rarely found in terrestrial organisms but common in natural products from marine organisms) from chlortetracycline. This third antibacterial agent was subequently found naturally as a constituent of both Streptomyces aureofaciens and Streptomyces viridifaciens. The structures of chlortetracycline were established by R.B. Woodward in 1952 and that of oxytetracycline by Pfizer scientists (in collaboration with RBW) in 1952. 

Tetracyclines were the first broad-spectrum antibiotics and have been used successfully for decades to treat both gram-positive and gram negative bacterial infections (82). Chlortetra-cycline was the first tetracycline to be isolated, in 1948, from Streptomyces aureofaciens (83). Other common tetracyclines, such as oxytet-racycline and tetracycline, were isolated from Streptomyces sources in subsequent years. The abundance of natural, active tetracyclines, coupled with extensive synthetic alterations, provides a rich collection of compounds from which to build meaningful structure-activity relationships. As was found for the aminoglycosides, previous observations of tetracycline structure and activity can be rationalized from recent tetracycline/30S crystal structures (11,12). 

Tetracyclines are a group of antibiotics derived from bacteria. Chlortetracycline was isolated from Streptomyces aureofaciens and... 

Tetracycline is produced by fermentation of Streptomyces aureofaciens and related species or by catalytic reduction of chlortetracycline. The blood levels achieved on oral administration often are irregular. Food and milk lower absorption by approximately 50%. 

Demeclocycline lacks the C-6-methyl of tetracycline and is produced by a genetically altered strain of Streptomyces aureofaciens. Because it is a secondary alcohol, it is more chemically stable than tetracycline against dehydration. Food and milk co-consumption decrease absorption by half, although it is 60 to 80% absorbed by fasting adults. It is the tetracycline most highly associated with phototoxicity and has been shown to produce dose-dependent, reversible diabetes insipidus with extended use. 

The tetracyclines (Table 1.15) are a large family of antibiotics, the first members of which were derived from the Streptomyces genus of Actinobacteria. Chlortetracycline was isolated from Streptomyces aureofaciens in 1944, and a few years later, oxytetracycline and demeclocycline were... 

Tetracycline also can be produced by Streptomyces aureofaciens fermentations under special conditions, that is, chloride starvation or special strains of the organism that fail to halogenate efficiently. Tetracycline possesses many chemotherapeutic properties of chlortetracycline and oxytetracycline. It is an important broad-spectrum antibiotic. 

In connection with work on animal protein factors, it was found that chlortetracycline fermentation mash containing some vitamin Bi2 gave growth responses well above those obtained with supraoptimal levels of vitamin Bi2 alone. At the present time, both chlortetracycline and oxytetracycline are used extensively for growth stimulation and improvement of feed efficiency in poultry and hogs, and for the reduction of losses from certain disease conditions. Purified antibiotics as well as dried fermentation residues with the mycelium of Streptomyces aureofaciens are used for these purposes. Tetracyclines, used as animal feed supplements, are selling for about 60/kg. 

Demethyl-7-chlortetracycline Streptomyces aureofaciens + + Rickettsia Tetracycline Parenteral and oral... 

McCormick, J. R. D., U. Hirsch Joachim, E. R. Jensen, S. Johnson, and N. O. Sjolander Biosynthesis of the tetracyclines. VII. 4-hydroxy-6-methylpretetra-mid, an intermediate accumulated by a blocked mutant of Streptomyces aureofaciens. J. Am. Chem. Soc. 87, 1793 (1965b). 

Tetracycline 4.30) and its derivatives are the most used of all broad-spectrum antibiotics . Their selectivity depends on their preferential accumulation by bacteria, as was outlined in the introduction to Chapter 3. Chelation of magnesium also plays an important part in their action, and this is discussed in Section 11.8. Tetracycline is prepared by the dechlorination of its 7-chloro-derivative ( Aureomycin ), the first medicinal tetracycline, isolated in 1947 from Streptomyces aureofaciens. It is a dimethyl-aminopentahydroxydioxo-octahydrowajprAac w carboxamide. 

Tetracycline Tetracycline, 4-dimethylamino-l,4,4a,5,5a,6,ll,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-l,ll-dioxo-2-naphthacencarboxamide (32.3.3), is synthesized by reducing chlorotetracycline with hydrogen using a palladium on carbon catalyst. However, it can be synthesized microbiologicaUy using the actinomycete Streptomyces viridifaciens, as well as a certain mutant S. aureofaciens [206-214]. 

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