Benzylpenicillin fermenter

PhCHa benzylpenicillin = penicillin G (usual fermentation product)... 

The acylation of 6-APA (Scheme 59) has been a very versatile way in which to generate new penicillin derivatives which differ from fermentation-produced penicillins in the 6-side chain. As will be discussed in Section 5.11.5.1, this approach has led to significant improvements in the therapeutic properties of penicillins, and, in fact, of the penicillins in medical use today, only benzylpenicillin and phenoxymethylpenicillin are produced directly by fermentation. 

Following the realization that the presence of phenylacetic acid in the fermentation led to a simplification of the mixture of penicillins produced by the fungus due to preferential uptake of this acid and its incorporation into benzylpenicillin (4), a wide variety of other acids were added to the growing culture. Inclusion of the appropriate acids in the culture medium thus afforded, respectively, phenoxymethylpenicillin (5, penicillin V), phenethicillin propicillin (7), and phehbencillin... 

Naturally occurring. For example, those produced by fermentation of moulds such as Penicillium notatum and P. chrysogenum. The most important examples are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). 

The manufacture of benzylpenicillin (penieillin G, originally just penicillin ) is chosen as a model for the antibiotic production process. It is the most renowned of antibioties and is the first to have been manufactured in bulk. It is still universally prescribed and is also in demand as input material for semisynthetic antibiotics (Chapter 5). Developments associated with the penicillin fermentation process have been a significant factor in the development of modem bioteehnology. It was a further 30 years, i.e. not until the 1970s, before there were signifieant new advances in industrial fermentations. 

The production of benzylpenicillin is very sensitive to temperature. A lot of metabolic heat is generated and the fermentation temperature has to be reduced by controlled cooling. This heat transfer is achieved by circulating chilled water through banks of pipes inside the vessel (which also serve as baffles) or through external limpet coils on the jacket of the vessel. These coils consist of continuous lengths of pipe welded in a shallow spiral round the vessel. This cooling water system is also used to cool batched medium sterilized in the vessel prior to its inoculation. 

The simplest way to complex organic compounds is by fermentation. Three very important antibiotics, benzylpenicillin (1), oxytetracycline (2) and erythromycin A (3) are all produced by fermentation in ton quantities at a price of less than U.S. 10 per kg. 

In a multiphase membrane reactor, the conversion of benzylpenicillin to 6-aminopenidllinic acid is performed. The type of microstructured reactor used is a fermentation reactor which contains the enzyme penicillin acylase immobilized on the wall of a hollow-fiber tube. The hollow-fiber tube extracts 6-aminopenicillinic acid at the same time selectively. Benzylpenicillin is converted at the outer wall of the hollow fiber into the desired product, which passes into the sweep stream inside the fiber where it can be purified, e.g. by ion exchange. The non-converted benzylpenicillin is recycled back through the reactor [84],... 

Several natural penicillins can be produced, depending on the chemical composition of the fermentation medium used to culture penicillium. Penicillin G (benzylpenicillin) has the greatest antimicrobial activity of these natural penicillins and is the only natural penicillin used clinically. However, penicillin G is not stable it is extremely acid-labile. Only about one-third of an oral dose is absorbed under the most ideal conditions. Therefore, it is generally not given orally but is administered by intramuscular injection. Several newer derivatives of penicillin G have been developed that do have good to excellent oral absorption (e.g., cloxacillin, ampicillin, and amoxicillin). 

Like benzylpenicillin, penicillin V is still used in its own right, but can also be used as a starting material for the manufacture of semisynthetic penicillins which cannot be made by direct fermentation. 

It is possible to convert penicillin V or benzylpenicillin to a cephalosporin by chemical ring expansion. The first-generation cephalosporin cephalexin, for example, can be made in this way. Most cephalosporins used in clinical practice, however, are semi-synthetics produced from the fermentation product cephalosporin C. 

Manufacturing processes for cephalosporin C and benzylpenicillin are broadly similar. In common with many other antibiotic fermentations, no specific precursor feed is necessary for cephalosporin C. There is sufficient acetyl group substrate available from the organism s metabolic pool for the terminal acetyltransferase reaction. 

Both benzylpenicillin and phenoxymethy1 penicillin are produced commercially by fermentation. However, from the beginning of the vast British-American cooperative program during World... 

During the same period, Sheehan was working toward a total synthesis of penicillins. In 1958, he announced the synthesis of 6-amino-penicillanic acid (6-APA) and its utility for the preparation of new penicillins by acylation (67, 68). (Almost 10 years earlier, this substance had been postulated to be an intermediate in the biosynthesis of penicillins (69, 70). Prior Japanese literature also contained clear suggestions that it had been formed by enzymatic hydrolysis of benzylpenicillin (71) and in fermentations carried out in the absence of side chain precursors... 

The protein contaminants in benzylpenicillin derive from the fermentation manufacturing processes used in production of the antibiotic. During the course of fermentation, proteins of the medium become penicilloylated and may be extracted in minute amounts into the final preparations. The semisynthetic penicillins are prepared from 6-APA, which in turn is obtained through either enzymatic or chemical removal of the side chain in benzylpenicillin (Carrington 1971). Penicil-... 

The penicillins and cephalosporins, collectively known as beta-lactam antibiotics, are among the most widely used and valuable antibiotics currently available. Ben-zylpenicilhn (penicillin G) and phenoxymethylpenicillin (penicillin V) are derived from Penicillium molds by fermentation, while half-synthetic penicillins are derived by chemical modification of the penicillin nucleus, 6-aminopenicillanic acid (6-APA), itself obtained either by splitting the side chain from benzylpenicillin through an enzymatic process or via a chemical deacylation reaction. 

Aminopenicilloic acid reacts with proteins to produce the penicoyl determinant (Batchelor et al. 1962, 1965 Moss 1964) (Fig. 7). However, since it has been shown that most samples of 6-APA also contain benzylpenicilloylated proteins derived from the fermentation procedure used to prepare benzylpenicillin (Batchelor et al. 1967 Stewart 1967), early studies claiming immunogenicity of 6-APA (de Weck and Eisen 1960 Chisholm et al. 1961 Stewart 1962 Wagelie et al. 1963) should be reevaluated. Purified 6-APA is apparently only weakly immunogenic in rabbits (Dewdney et al. 1971). 

Aminopenicillanic acid (6 APS) is an important precursor for the organic synthesis of new P. The compound itself has no antibiotic activity it is isolated as a fermentation product from cultures of Pen-cillium chrysogenum, or prepared by the enzymatic hydrolysis of benzylpenicillin. Thousands of new P. have been prepared by the acylation of 6 APS, but only a few of these are therapeutically useful, e.g Penicillin V is relatively stable to acid and is not hydrolysed in the stomach, so that it may be administered in tablet form Ampicillin (the aminophenyl-acetyl derivative of 6 APS), has a wider spectrum of activity than most other R, including activity against various Gram-negative bacteria (Typhus, E. coli, etc.). 

An interesting use of mixed radioisotope and stable isotope labelling was demonstrated when the formation of benzylpenicillin by Penicillium chryso-genum in the presence of L- and D-[3- C, N, S]cystine was studied. The penicillin isolated contained the three labels in their proportions in the precursor when L-cystine had been added to the fermentation medium. It was concluded that cystine was a direct precursor of penicillin, probably after reduction to cysteine [215]. 

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