Chloramphenicol production

Z. U. Ahmed and L. C. Vining, Evidence for a chromosomal location of the genes coding for chloramphenicol production in Streptomyces venezuelae, J. Bacteriol., 154 (1983) 239-244. 

Most remarkably, catalyst loadings could be reduced to 1.25 mol%, resulting in total turnover numbers > 50 (Table 6.3) [247]. Catalyst 233 is readily available in large quantities because its synthesis is based on (S,S)-(+)-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane, an intermediate of industrial chloramphenicol production... 

Thus for instance its biosynthesis [5] was investigated with the aid of stable isotopes (2H, 13C), in experiments in which acetic acid or dichloroacetic acid served as precursors. In streptomyces it was found that the addition of amino acids such as phenylalanine, or P-nitrophenylserine increases the chloramphenicol production. In further experiments NaCl was replaced with NaBr and bromo and chloroderivatives could be isolated from the cultivation broth [6]. 

Chatterjee, S., Vining, L. C., 1982a, Catabolite repression in Streptomyces venezuelae. Induction of 3-galactosidase, chloramphenicol production, and intracellular cyclic adenosine 3, 5 monophosphatase concentrations. Can. J. Microbiol. 28 311. 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

In 1939 the isolation of a mixture of microbial products named tyrotbricin from a soil bacillus was described. Further investigation showed this material to be a mixture of gramicidin and tyrocidine. In rapid succession the isolation of actinomycin (1940), streptothricin (1942), streptomycin (1943), and neomycin (1949), produced by Streptomjces were reported and in 1942 the word antibiotic was introduced. Chloramphenicol, the first of the so-called broad spectmm antibiotics having a wide range of antimicrobial activity, was discovered in 1947. Aureomycin, the first member of the commercially important tetracycline antibiotics, was discovered in 1948. 

Plasmid-mediated bacterial inactivation of chloramphenicol and thiamphenicol can potentially lead to three products, the 3- 0-acetyl (3), 1-0-acetyl (4), and 1,3-di-O-acetyl (5) derivatives as shown in Figure 1. 

Toxic Effects on the Blood-Forming Tissues Reduced formation of erythrocytes and other elements of blood is an indication of damage to the bone marrow. Chemical compounds toxic to the bone marrow may cause pancytopenia, in which the levels of all elements of blood are reduced. Ionizing radiation, benzene, lindane, chlordane, arsenic, chloramphenicol, trinitrotoluene, gold salts, and phenylbutazone all induce pancytopenia. If the damage to the bone marrow is so severe that the production of blood elements is totally inhibited, the disease state is termed aplastic anemia. In the occupational environment, high concentrations of benzene can cause aplastic anemia. 

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 ver)ezuelae 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 therefrom tne desired chloramphenicol. 

The synthetic route to chloramphenicol is described in U.S. Patent 2,4B3,BB4 as follows 1.1 g of sodium is dissolved in 20 cc of methanol and the resulting solution added to a Solution of 5 g of benzaldehyde and 4.5 g of /3-nitroethanol in 20 cc of methanol. After standing at room temperature for a short time the gel which forms on the mixing of the reactants changes to a white insoluble powder. The precipitate is collected, washed with methanol and ether and then dried. The product thus produced is the sodium salt of... 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Enterohepatic circulation can lead to toxic effects. For example, the drug chloramphenicol is metabolized to a conjugate that is excreted in bile by the rat. Once in the gut, the conjugate is broken down to release a phase 1 metabolite that undergoes further metabolism to yield toxic products. When these are reabsorbed, they can cause toxicity. The rabbit, by contrast, excretes chloramphenicol conjugates in urine, and there are no toxic effects at the dose rates in question. 

Chloramphenicol (CAP) is a broad-spectrum antibiotic that was widely used in veterinary medicine. Since 1994 the use of CAP is banned in the EU because of certain toxicological problems (i.e., aplastic anemia and the grey baby syndrome ) observed in its administration to humans [ 107] that have prompted the establishment of a zero tolerance for the presence of these residues in meat and animal products. As a consequence, many efforts have been made to develop sensitive methodologies capable of detecting CAP residues or its metabolites. 

Various microbiological processes are used in the production of a number of antibiotics, for instance penicillins, tetracyclines, chloramphenicol and streptomycins. The major areas of such operations being ... 

Chloramphenicol [20 CAP D-(—)-ft reo-l-(p-nitrophenyl)-2-(dichloroacetamido)-l,3-propanediol] is an important antibiotic due to its broad activity against a number of clinically relevant microbial pathogens and its ability to penetrate easily the blood-brain barrier. Besides human application, CAP became widely and routinely used in veterinary practice and is used in Europe in most animal productions including fish128. 

The most important example to be discussed here is that of the drug chloramphenicol (11.39, R = 2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophen-yl)ethyl, Fig. 11.7), the many metabolic pathways of which have yielded a wealth of information [75], The dichloroacetyl moiety is especially of interest in that dechlorination proceeds by three proven routes glutathione-dependent dechlorination, cytochrome P450 catalyzed oxidation, and hydrolysis. Of particular value is that the oxidative and hydrolytic routes can be unambiguously distinguished by at least one product, as shown in Fig. 11.7. Oxidation at the geminal H-atom produces an unstable (dichloro)hydroxyacet-amido intermediate that spontaneously eliminates HC1 to yield the oxamoyl... 

In contrast to oxidative dechlorination, the hydrolytic dechlorination of chloramphenicol replaces a Cl-atom with a OH group to yield a (monochlo-ro)hydroxyacetamido intermediate. The latter, like the dichloro analogue, also eliminates HC1, but the product is an aldehyde that is far less reactive than the oxamoyl chloride intermediate. Chloramphenicol-aldehyde undergoes the usual biotransformation of aldehydes, namely reduction to the primary alcohol 11.41 and dehydrogenation to the oxamic acid derivative 11.40 (Fig. 11.7). 

Chloramphenicol is a broad-spectrum antibiotic indicated for superficial eye infections. Products containing corticosteroids should not be used in undiagnosed red eye since the administration of the corticosteroid may remove the symptoms although the condition may not be addressed. 

Some other antibiotics commonly used in animal production such as the bacitracins, bambermycins and virginiamycins as well as the streptomycins are poorly absorbed from the intestinal tract and residues usually do not occur from feeding. Chloramphenicol is used illegally in the United States in many species it is used legally in Europe, Canada and other parts of the world. 

As a group, the protein biosynthesis inhibitors comprise the second largest class of antibiotics available for clinical use. Natural product classes of antibiotics that inhibit the protein biosynthesis are aminoglycosides, tetracyclines, chloramphenicol, macrolides, lincosamides, fusidic acid, streptogramins and mupirocin (Fig. 7). 

Drugs that may affect repaglinide include CYP 450 inhibitors (eg, clarithromycin, erythromycin, ketoconazole, miconazole), CYP 450 inducers (eg, barbiturates, carbamazepine, rifampin), beta blockers, calcium channel blockers, chloramphenicol, corticosteroids, coumarins, estrogens, gemfibrozil, isoniazid, itraconazole, levonorgestrel and ethinyl estradiol, MAOIs, nicotinic acid, NSAIDs, oral contraceptives, phenothiazines, phenytoin, probenecid, salicylates, simvastatin, sulfonamides, sympathomimetics, thiazides and other diuretics, and thyroid products. 

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