Tetracyclines from Streptomyces aureofacien

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 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... 

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... 

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 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. 

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. 

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... 

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. 

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. 

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