Cephalosporium acremonium strain

Zhou W, Holzhauer-Rieger K, Bayer T, Schugerl K, Cephalosporin C. production hy a highly productive Cephalosporium acremonium strain in an airlift tower loop reactor with static mixers. J Biotechnol 28(2-3) 165-177, 1993. 

Zhang J, Wolfe S, Demain A L (1988). Phosphate repressible and inhibitible P-lactam synthetases in Cephalosporium acremonium strain C-10. Appl. Microbiol. Biotechnol. 29 242-247. 

Cephalosporins (Figure 3.10) are penicilHn-related group of antibiotics derived from cephalosporin C, 115a, an antibiotic isolated from a Cephalosporium acremonium strain by Giuseppe Brotzu in 1945. Its structure was elucidated by Newton and Abraham in 1961 [90]. Cephalosporins contain the 7-aminocephalosporanic acid nucleus (7-ACA), 115c that consists of a fused P-lactam-dihydrothiazine system, also known as cephem, with the lowest numbered position of the double bond being specified by prefixes (cephalosporins are 3-cephems or A -cephems) [91]. 

In 1945 it was noted that a strain of Cephalosporium acremonium i oAu ced antibiotic material that was active against gram-negative as weU as gram-positive... 

The ancestral strain of Acremonium chrysogenum (at that time called Cephalosporium acremonium) was isolated on the Sardinian coast in 1945 following an observation that the local sewage outlet into the sea cleared at a quite remarkable rate. Advances were slow because the activity was associated with a number of different types of compound. Cephalosporin C was first isolated in 1952, but it was a further decade before clinically usefiil semisynthetic cephalosporins became available. 

Cephalosporin C (Figure 7.37) is produced commercially by fermentation using cultures of a high-yielding strain of Acremonium chrysogenum (formerly Cephalosporium acremonium). Initial studies of the antibiotic compounds synthesized by C. acremonium identified penicillin N (originally called cephalosporin N) as the major component, with small amounts of cephalosporin C. In contrast to the penicillins, cephalosporin C was stable under acidic conditions and also was not attacked by penicillinase ((5-lactamase). Antibacterial activity was rather low, however, and the antibiotic was poorly absorbed after oral administration. However, the structure offered considerable scope for side-chain modifications, more so than with the penicillins since it has two side-chains, and this has led to a wide variety of cephalosporin drugs, many of which are currently in clinical use. As with the penicillins, removal of the amide... 

L Mathison, C Soliday, T Stepan, T Aldrich, J Rambosek. Cloning, characterization, and use in strain improvement of the Cephalosporium acremonium gene cefG encoding acetyl transferase. Curr Genet 23 33 41, 1993. 

DJ Hook, LT Chang, RP Elander, RB Morin. Stimulation of the conversion of penicillin N to cephalosporins by ascorbic acid, a-ketoglutarate and ferrous ions in cell-free extracts of strains of Cephalosporium acremonium. Biochem Biophys Res Commun 87 258-265, 1979. 

PL Skatrud, SW Queener. An electrophoretic molecular karyotype for an industral strain of Cephalosporium acremonium. Gene 78 331-338, 1989. 

The thiazine lactones (336) have been made by reduction of the thiazines (335) <85TL745,87T2709). A similar thiazine lactone (337) has been isolated from cultures of a cephalosporin C producing strain of Cephalosporium acremonium <88TL2101>. 

Cephalothin is a semisynthetic P-lactam antibiotic prepared by the reaction of thio-phene-2-acetyl chloride with 7-aminocephalos-poranic acid (7-ACA). The cephalosporanic nucleus is obtained from cephalosporin C which is produced by a fungus identified as Cephalosporium acremonium No. +9137 (Imperial Mycologi-cal Institute, England), or strains thereof. 

The anti-bacterial activity of the penicillins stimulated a major search for other antibiotics. Many compounds were isolated from amongst the metabolites of Streptomycetes obtained from soil. These included therapeutically useful antibiotics such as chloramphenicol, the tetracyclines, erythromycin and streptomycin. Several fungi yielded useful compounds. One of these was Cephalosporium acremonium. A biologically-active strain was obtained by Brotzu from a sewage outfall near Cagliari in Sardinia in 1945 and described in 1946. The p-lactam cephalosporin C (1.23) was isolated from this organism in 1954 and its structure determined in 1961 by Abraham and Newton. 

Helvolic acid (5.145) was the first of the steroidal fusidane antibiotics to be isolated. It was obtained from Aspergillus fumigatus var helvola in 1943 by Chain and Florey. Cephalosporin Pi (5.146) was deseribed by Abraham as a metabolite of the same Brotzu strain of Cephalosporium acremonium as that... 

The novelty of this structure coupled with its interesting spectrum of antibacterial activity were clearly of potential commercial interest, and this time there were no qualms about patenting the discoveries. The strain of Cephalosporium acremonium was made the property of the National Research Development Corporation (NRDC) in Britain, and over the course of the next 15 years or so, this body received (on behalf of the British government) a fortune in royalties for the development of the cephalosporin antibiotics. 

Zhou W, Holzhauer-Rieger K, Dors M, Schugerl K. Influence of medium composition on the cephalosporin C production with a highly productive strain Cephalosporium acremonium. J Biotechnol 23(3) 315—329, 1992b. 

L-a-Aminoadipic acid plays an essential role in bio nthesis, although in the assembled end-product it appears in the D form. Incorporation studies employing a-[6- C]aminoadipic acid show that the incorporation of the L isomer is considerably faster than that of the D isomer [279]. According to studies carried out on mutant strains of Cephalosporium acremonium, if the common lysine—L-a-aminoadipic acid metabolism is inhibited before the latter, then besides lysine the internal addition of a-aminoadipic acid is necessary to make the microorganisms capable of synthesizing -lactam antibiotics [271]. 

Hook, D. J., L. T. Chang, R. P. Elander, and R. B. Morin Stimulation of the Conversion of Penicillin N to Cephalosporin by Ascorbic Acid, a-Ketoglutarate, and Ferrous Ions in Cell-Free Extracts of Strains of Cephalosporium acremonium. Biochem. Biophys. Res. Commun. 87, 258 (1979). 

Soon after the penicillins were introduced into practice, penicillin-resistant strains of bacteria began to appear and have since proliferated. One approach to combating resistant strains is to synthesize newer, more effective penicillins, such as ampicillin, methicillin, and amoxicillin. Another approach is to search for more effective )8-lactam antibiotics. At the present time, the most effective are the cephalosporins, the first of which was isolated from the fungus Cephalosporium acremonium. These antibiotics have an even broader spectrum of antibacterial activity than penicillins and are effective against many penicillin-resistant bacteria, although resistance to cephalosporins is becoming widespread. 

Fawcett, P. A., P. B. Loder, M. J. Duncan, T. J. Beesley, and E. P. Abraham Formation and Properties of Protoplasts from Antibiotic-Producing Strains of Penicillium chrysogenum and Cephalosporium acremonium. J. Gen. Microbiol. 79, 293 (1973). 

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