Chloramphenicol from Streptomyces venezuelae

Chloramphenicol (Fig. 10.72) was originally isolated from Streptomyces Venezuela, but is now prepared synthetically. It has two chiral centres, but only the i ,i -isomer is active. 

Chloramphenicol 4.45) isolated from Streptomyces venezuelae in 1947 but now obtained entirely by synthesis, is the T>- -)threo isomer of 2,2-dichloro-iV-[2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophenyl)ethyl] acetamide. Its selective antibacterial effect, when given orally, depends on its inhibition of protein synthesis on the ribosomes of bacteria without affecting that taking place on mammalian ribosomes, even when it has free access to the latter (Rendi and Ochoa, 1962). The other three stereoisomers have no effect on protein synthesis. 

Nowadays, we have a wide range of antibiotics at our disposal. In general, these may be grouped into the following classes of compounds amino-glycosides, jS-lactams, chloramphenicol (first isolated from Streptomyces venezuelae), glycopeptides e.g. vancomycin), lincomycin, macrolides, polyethers and tetracyclines. 

Chloramphenicol (at right) is a potent antibiotic, isolated from Streptomyces venezuelae, that is particularly effective against typhoid fever. It was the first naturally occurring substance shown to contain a nitro (— NO2) group attached to an aromatic ring. Both chirality centers in chloramphenicol are known to have the (/ ) configuration. Identify the two chirality centers and write a three-dimensional formula for chloramphenicol. 

Chloramphenicol an antibiotic, M, 323, from Streptomyces venezuelae. There are 4 stereoisomers, of which only D(-)-threo-C. (Fig.) is an antibiotic. C. inhibits protein synthesis on 70S ribosomes of prokaryotes, and on the mitochondrial ribosomes of eukaryotic cells. Protein synthesis on SOS eukaryotic ribosomes is not affected. C. inhibits peptide bond formation and peptidyl transferase activity on the 50S ribo-somal subunit, by specifically binding to one of the SOS ribosomal proteins involved in these reactions. The protein in question is probably localized in the acceptor-donor region of the ribosome. C. is used as a broad-spectrum antibiotic in the treatment, e.g. of typhoid fever, paratyphus, spotted fever, infectious hepatitis, dysentery, phtheiia and viral influenza . Because it inhibits protein synthesis in mitochondrial ribosomes, C. is relatively toxic. It is now produced entirely synthetically. 

Chloramphenicol was originally obtained from Streptomyces Venezuela but is now produced by chemical synthesis. Although it has a broad spectrum of activity, it is rarely used systemically due to a high incidence of aplastic anaemia. 

Chloramphenicol may be prepared by fermentation or by chemical synthesis. The fermentation route to chloramphenicol is described in U.S. Patents 2,4B3,B71 and 2,4B3,B92. To quote from U.S. Patent 2,4B3,B92 The cultivation of Streptomyces venezuelae may be carried out in a number of different ways. For example, the microorganism may be cultivated under aerobic conditions on the surface of the medium, or it may be cultivated beneath the surface of the medium, i.e., in the submerged condition, if oxygen is simultaneously supplied. 

Chloramphenicol, a powerful antibiotic isolated in 1949 from the Streptomyces venezuelae bacterium, is active against a broad spectrum of bacterial infections and is particularly valuable against typhoid fever. Assign R,S configurations to the chirality centers in chloramphenicol. 

Chloramphenicol is a highly active antibiotic that was first isolated from cultures of Streptomyces venezuelae but is now produced synthetically. It is unique among natural compounds in that it contains a nitrobenzene moiety. Chloramphenicol has been used both in treatment and prophylactically in food-producing animals for over 40 years, administered orally with the feed or drinking water to poultry, veal calves, swine, sheep, and lambs, and intramuscularly or intravenously to sheep, goats, pigs, and calves at a dosage of 2-4 mg/kg bw. In several countries, chloramphenicol has been also used in fish for the treatment of furunculoses on salmonids (22). 

Briefly stated, the production of chloramphenicol by the surface culture method involves inoculating a shallow layer, usually less than about 2 cm, of a sterile, aqueous nutrient medium with Streptomyces venezuelae and incubating the mixture under aerobic conditions at a temperature between about 20° and 40°C, preferably at room temperature (about 25°C), for a period of about 10 to 15 days. The mycelium is then removed from the liquid and the culture liquid is then treated by methods described for isolating there... 

Chlorinated derivatives are the most Sequent halogenated metabolites found in the nature. This is mainly due to the fact that chlorine is the most common halogen found on the Earth. Chloramphenicol, isolated from the soil bacterium Streptomyces venezuelae, was the very first halogenated metabolite detected. This important commercial antibiotic will be dealt with in chapter 1. Other chlorinated metabolites, e.g. chlortetracycline, will be discussed in chapter 2. 

Chloramphenicol phosphotransferase from the producing bacterium Streptomyces venezuelae (47) is unrelated to the protein kinase family but rather shows more similarity to small-molecule kinases such as shikimate kinase (48). Analogous to the CAT strategy, phosphorylation occurs at the hydroxyl position 3, blocking this essential group from interacting with the ribosome (Fig. 10). 

Almost contemporaneous with these discoveries, scientists at Parke Davis in Detroit were also studying soil samples from all over the world. These were evaluated at Yale University, and in 1947 they isolated a novel structure from a soil sample taken from near Cararcas in Venezuela. This was, unsurprisingly, christened Streptomyces venezuelae, and the antibiotic was given the name chloramphenicol. Its relatively simple chemical structure was elucidated in 1947, and it was also first used in that year to treat 22 seriously ill... 

There are also a large number of antibiotics structurally unrelated to penicillins and cephalosporins. These compounds exert their antimicrobial activity by inhibiting protein biosynthesis. In 1947 chloramphenicol (see Figure 3) was isolated from cultures of Streptomyces venezuelae. It is a broad-spectrum bacteriostatic agent that interferes with protein synthesis by binding to bacterial ribosomes. The use of chloramphenicol in humans is hmited because of the drug s toxicity. It inhibits liver enzymes and suppresses red blood cell formation. 

Structurally related to (D)-(-)-pseudoephedrine (shown In red) Is the antibiotic chloramphenicol, isolated from the filamentous Gram-positive bacterium Streptomyces venezuelae, and used to treat bacterial conjunctivitis topically and in certain cases also meningitis systemically. 

Chloramphenicol (Parke-Davis, 1949) was obtained from the soil bacterium Streptomyces venezuelae. Its use as a systemic treatment is restricted to very severe infections such as typhoid fever when careful clinical assessment indicates that no other antibiotic is effective. This is because it is known to have toxic effects on bone marrow. However, it is used topically for infections of the ear, skin and eye. Its mode of action is by the inhibition of bacterial protein synthesis. 

Chloramphenicol is an antibiotic isolated from the Streptomyces venezuelae bacterium. Predict the expected isotope pattern in the mass spectrum of this compound (the relative heights of the molecular ion peak and surrounding peaks). 

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