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Production of antibiotics

Benzylpenicillins and phenoxymethylpenicillins (penicillins G and V, respectively) are produced by fermentation and are the basic precursors of a wide range of semi-synthetic antibiotics, e.g. ampicillin. The amide link may be hydrolysed conventionally but the conditions necessary for its specific hydrolysis, whilst causing no hydrolysis of the intrinsically more labile but pharmacologically essential b-lactam ring, are difficult to attain. Such specific hydrolysis may be simply achieved by use of penicillin amidases (also called penicillin acylases). Different enzyme preparations are generally used for the hydrolysis of the penicillins G and V, pencillin-V-amidase being much more specific than pencillin-G-amidase.

Penicillin amidase may be obtained from E. coli and has been immobilised on a number of supports including cyanogen bromide-activated Sephadex G200. It represents one of the earliest successful processes involving immobilised enzymes and is generally used in batch or semicontinuous STR processes (40,000 Ukg^-1penicillin G, 35°C, pH 7.8, 2 h) where it may be reused over 100 times. It has also been used in PBRs, where it has an active life of over 100 days, producing about two tonnes of 6-aminopenicillanic acid kg^-1of immobolised enzyme.

  [5.8]

[5.9]

The penicillin-G-amidases may be used 'in reverse' to synthesise penicillin and cephalosporin antibiotics by non -equilibrium kinetically controlled reactions (see also Chapter 7). Ampicillin has been produced by the use of penicillin-G-amidase immobilised by adsorption to DEAE -cellulose in a packed bed column:

    [5.10]

Many other potential and proven antibiotics have been synthesised in this manner, using a variety of synthetic b-lactams and activated carboxylic acids.

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