Antibiotics produced by fermentation

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). 

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. 

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. 

Pharmaceutical. Ion-exchange resins are useful in both the production of pharmaceuticals (qv) and the oral adrninistration of medicine (32). Antibiotics (qv), such as streptomycin [57-92-17, neomycin [1404-04-2] (33), and cephalosporin C [61-24-5] (34), which are produced by fermentation, are recovered, concentrated, and purified by adsorption on ion-exchange resins, or polymeric adsorbents. Impurities are removed from other types of pharmaceutical products in a similar manner. Resins serve as catalysts in the manufacture of intermediate chemicals. 

To obtain reproducible antibiotic production by fermentation, it is necessary to obtain a pure culture of the producing organism. Pure cultures are isolated from mixed soil sample populations by various streaking and isolation techniques on nutrient media. Once a pure culture has been found that produces a new antibiotic typically on a mg/L scale, improvement in antibiotic yield is accompHshed by modification of the fermentation medium or strain selection and mutation of the producing organism. Production of g/L quantities may take years to accomplish. 

Antibiotics are produced by fermentation. The process may take a few days to obtain an extractable amount of product. Antibiotic production is done by the batch process. Oxygen transport is the major concern therefore sufficient polymeric sugar and protein with a trace amount of elemental growth factors are used to enhance production. An anti-biogram test is used to observe the amount of antimicrobial agent in the fermentation broth. A bioassay determines the activity unit of the bactericides. 

Antibiotics, regardless of method of manufacture Certain substances produced by fermentation Disaccharidase inhibitors HMG-CoA inhibitors Synthetic chemicals... 

The concept of impurity profiling is very important for antibiotics, since most of them are still produced by fermentation or by semisynthesis starting from fermentation products. Antibiotics are typically complex mixtures of several components and their composition depends on the fermentation conditions. Impurities due to degradation occur frequently. Commercial samples usually contain significant amounts of impurities with only minor structural differences among them, but differing widely in their pharmacological activities. These impurities can exhibit antibiotic activity, but in many cases they are inactive and sometimes even toxic. The applicability of CE in the analysis of antibiotics has been reviewed elsewhere. The use of CZE in impurity analysis of antibiotics is discussed in detail below. 

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. 

However, it was not until 1971, when Gross and Morrell reported the structure elucidation of the purified nisin peptide, 12 that it became clear that nisin contained Lan and MeLan residues. Since nisin is an important peptide antibiotic, regularly used in the food production industry as a preservative (preservative EC 234), it has attracted a great deal of attention. Nisin is produced by fermentation, however, partly because of its intriguing structure, it also became the target for the only complete synthesis of a lantibiotic reported to date in the literature. This work has been reviewed. 13 14 ... 

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. 

Fermentation. Fermentation is defined (Ref 3) as the production of chemicals by a series of enzyme catalyzed reactions with bacteria, yeasts, or molds under aerobic or anaerobic conditions. At present, fermentation is used to produce complex molecules not easily synthesized such as penicillin and other antibiotics, vitamin BI2, and enzymes. Formerly, glycerine (See Fetmentol), acetone, butanol, and citric lactic acids were some of the chemicals produced by fermentation process. Synthesis is now a more economical route to these materials (See also Refs 1 2) Refs 1) P.A. Wells G.E. Ward, IEC 31, 172-77(1939) 2) H.E. Silcox S.B. Lee,... 

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. 

In the so-called tetracycline case (2), there was evidence that in the preparation of aureomycin broth by the fermentation of S, aureo-faciens, some small percentage of tetracycline was coproduced. Aureomycin was known and produced by fermentation substantially before the discovery of tetracycline. The argument was raised by the patent examiner when the tetracycline application was in the Patent Office that tetracycline must be produced inherently in the fermentation in the production of aureomycin. The applicant was able to show, however, that the amount of tetracycline produced in the fermentation broth in aureomycin production was so small that it was of inconsequential value to mankind as an antibiotic. In fact, most methods of analysis did... 

Corcoran JW (1981) Biochemical Mechanisms in the Biosynthesis of the Erythromycins. In JW Corcoran (eds) Antibiotics, Biosynthesis. Springer, Berlin, p 132 Rohr J, Zeeck A (1990) Biogenetic-Chemical Classification of Secondary Metabolites Produced by Fermentation. In RK Finn, P Prave (eds) Biotechnology Focus 2. Hanser Publishers, Munich, Vienna, New York, p 251... 

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