Fermentation, antibiotics produced

The modem fermentation industries developed from the early era of antibiotics. Over 4000 antibiotics have been discovered since the 1950s. However, only about 100 are produced on a commercial scale and over 40 of these are prepared by a combination of microbial synthesis and chemical modifications. Antibiotics produced by fermentation and used as starting materials in chemical syntheses are given in Table 2. 

Most of the fermentation and isolation processes for manufacture of the tetracyclines are described in patents (71,72). Manufacture begins with the cultivated growth of selected strains of Streptomjces in a medium chosen to produce optimum growth and maximum antibiotic production. Some clinically useful tetracyclines (2—4) are produced directly in these fermentations others (5—7) are produced by subjecting the fermentation products to one or more chemical alterations. The purified antibiotic produced by fermentation is used as the starting material for a series of chemical transformations (59). 

Prior to sterilizing the abovedescribed medium, adjust the pH to 8. Aerobically ferment for 66 to 90 hours while stirring at 250 rpm with air input at 4.5 C/)2/min and 25 psi. The potency of the antibiotic produced at the end of this period reaches a peak of 150 to 225 jug/ml and remains relatively constant. The pH of the fermentation medium changes slightly during the antibiotic production, varying in the range of 6.8 to 7.3. 

Furthermore, antibiotics produced by fermentation of various moulds or, espeeially, Streptomyces spp. can be employed by medieinal ehemists as starting bloeks in the production of what might be more effective antimierobial eompounds. 

In addition to chemical-based drugs, a range of pharmaceutical substances (e.g. hormones and blood products) are produced by/extracted from biological sources. Such products, some major examples of which are listed in Table 1.2, may thus be described as products of biotechnology. In some instances, categorizing pharmaceuticals as products of biotechnology or chemical synthesis becomes somewhat artificial. For example, certain semi-synthetic antibiotics are produced by chemical modification of natural antibiotics produced by fermentation technology. 

Oxanthromicin (79) (Figure 33) is an optically active antibiotic that has been isolated from the fermentation broth produced by Actinomadura sp. SCC 1646 ° . The results... 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluori-nation of erythromycin has been studied to ensure abetter stability in acidic medium and/or a better bioavailability. 

The flavor and body of cultured milks are distinguished by a delicate balance between components of the cultured product. Unless conditions of culture are carefully controlled, this balance may not be achieved even when pure cultures are employed. Empirical formulations relating to proper cultural and environmental conditions constitute the art of fermentations. Apart from problems arising from the use of improper conditions of culture, other defects may occur in the milk products because of contamination of a milk supply by unwanted organisms and because some organisms required in fermentations can produce antibiotics (bacteriocius). 

Hayashi M, Kim Y-P, Takamatsu S, Preeprame S, Komiya T, Masuma R, Tanaka H, Komiyama K, Omura S (1996) Chlovalicin, a New Cytocidal Antibiotic Produced by Sporothrix sp. FO-4649 I. Taxonomy, Fermentation, Isolation and Biological Activities. J Antibiot 49 631... 

Hoshino Y, Mukai A, Yazawa K, Uno J, Ishikawa J, Ando A, Fukai T, Mikami Y (2004) Transvalencin A, a Thiazolidine Zinc Complex Antibiotic Produced by a Clinical Isolate of Nocardia transvalensis I. Taxonomy, Fermentation, Isolation and Biological Activities. J Antibiot 57 797... 

Schimana J, Fiedler H-P, Groth I, Siissmuth R, Beil W, Walker M, Zeeck A (2000) Simocyclinones, Novel Cytostatic Angucyclinone Antibiotics Produced by Streptomyces antibioticus Tii6040 I. Taxonomy, Fermentation, Isolation and Biological Activities. J Antibiot 53 779... 

During the course of experiments for the elucidation of the structure of the two earlier discovered compounds chlortetracycline (CTC) and oxytetracycline (OTC) it was found that hydrogenation of chlortetracycline resulted in halogenolysis and the product tetracycline (TC) retained the useful activity spectrum of the first two members of the family. TC appears to represent the first clinically successful antibiotic produced by shere chemical manipulation of preexisting antibiotic. TC was found to be present in fermentations of both cultures streptomyces aureofaciens and streptomyces rimosus as well as in streptomyces viridofaciens (1). 

Fermentation processes produce a wide range of chemicals that complement the various chemicals produced by nonfermentation routes. For example, alcohol, acetone, butyl alcohol, and acetic acid are produced by fermentation as well as by synthetic routes. Almost all the major antibiotics are obtained from fermentation processes. 

High-Fructose Corn Syrup (HFCS) occurs as a water white to light yellow, somewhat viscous liquid that darkens at high temperatures. It is a saccharide mixture prepared as a clear, aqueous solution from high-dextrose-equivalent corn starch hydrolysate by the partial enzymatic conversion of glucose (dextrose) to fructose, using an insoluble glucose isomerase preparation that complies with 21 CFR 184.1372 and that has been obtained from a pure culture fermentation that produces no antibiotics. It is miscible in all proportions with water. 

Mitomycin C, an antibiotic produced by fermentation of streptomyces, has been used extensively in Japan for the treatment of stomach cancer which is prevalent in that country. It probably acts after conversion into an alkylating agent in vivo, and it also contains quinone and urethane moieties which may contribute to its anti-tumour effect. A related series of compounds, the pyrol-lizidine alkaloids, occur in a variety of plants and are known to cause acute liver cytotoxicity when accidentally ingested93). Like mitomycin C, these agents are almost certainly metabolised in vivo by liver microsomes to alkylating agents which cause the liver toxicity. Some of these alkaloids have antitumour properties, presumably because the active metabolite formed in the liver is stable enough to reach the tumour. 

Fermentation has produced natural products such as antibiotics and the cholesterollowering agents pravastatin and lovastatin. Modification of fermentation products has led to semisynthetic compounds such as simvastatin (see Figure 1.2), penicillins, and cephalosporins. With increased capability in genetic engineering,... 

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