Penicillin 6-amino penicillanic acid

Penicillins (A). The parent substance of this group is penicillin G (ben-zylpenidllin]. It is obtained from cultures of mold fungi, originally from Pen-icillium notatum. Penicillin G contains the basic structure common to all penicillins, 6-amino-penicillanic acid (p. 

Davies RJ, Hendrick DJ, Pepys J. Asthma due to inhaled chemical agents ampicillin, benzyl penicillin, 6 amino penicillanic acid and related substances. Clin Allergy 1974 4(3) 227-47. 

The term / -lactamase denotes an enzyme which catalyzes the hydrolysis of the amide bond in the /3-lactam ring of 6-amino-penicillanic acid (6-APA) or 7-amino-cephalosporanic acid (7-ACA) and of their A-acyl derivatives (2). Such derivatives are commonly referred to as penicillins [Fig. 1 (I) and cephalosporins Fig. 1 (III), (V), and (VII)], respectively. There is no evidence that any bond other than the amide bond in the intact nucleus of penicillin or cephalosporin is broken by the... 

When isopenicillin N, penicillin G, penicillin V, ampicillin, carboxy-w-bu-tyl penicillin, and 6-amino-penicillanic acid (6APA) were tested as substrate analogs [3,5,12], no ring expansion was observed. 

Solvent extraction of penicillin from fermentation broths has been well documented in the literature. Penicillin G and penicillin V can be efficiently extracted with amyl acetate or butyl acetate at pH 2.5-3.0 and at 0° to 3°C.33 Schiigerl1 systematically reviewed solvent extraction of different forms of penicillin from fermentation broths. Figure 1 shows an integrated process for the extraction of penicillin G from clarified broth of Penicillium chryso-genurn fermentation.1 Penicillin G is converted to 6-amino penicillanic acid and phenylacetic acid at pH 8 in a 10 L Kiihni extractor by penicillin G-amidase immobilized in an emulsion liquid membrane. The 6-amino penicillanic acid is subsequently converted to ampicillin at pH 6 and the enzyme is recycled. 

To date, the number of penicillin and cephalosporin-based molecules produced by semi- and total synthesis is well in excess of 20000. Most started with modification of the fermentation product, 6-amino-penicillanic acid 20 or the corresponding cephalosporin, 7-amino-cephalosporanic acid 21, both of which can be produced by simple chemical or biochemical deacylation from penicillin or cephalosporin C. The number above is only approximate as a significant proportion of structures from industry were never formally published, or were only mentioned in the patent literature—particularly if they had marginal or no significant activity levels over those which had been reported previously. 

Penicillin was the hrst P-lactam and the hrst broad-spectrum antibiotic discovered that started the Golden age (1940-1962) of antibiotics. The stmcture of penicillin contains a thiazolidine ring that is fused to a P-lactam ring. The existence and stability of the P-lactam ring was highly controversial at the time despite the availability of a single crystal X-ray structure of one of the penicillins. Penicillin G (8) was the first penicillin that was clinically used. Penicillin G was converted easily by either chemical or biochemical means to 6-amino-penicillanic acid (9),... 

Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semisynthetic penicillins with different properties. It is important to recognise that not all penicillins have the same antibacterial spectrum and that it is necessary to choose between a number of penicillins just as it is between antimicrobials of different structural groups, as is shown below. 

Iodometric methods for the assay of penicillins were first described by Alicino 9 in 1946. Penicillin is inert to iodine in neutral aqueous solution. But after hydrolysis with alkali or penicillinase, the resulting penicilloic acid (III) consumes from 6 to 9 equivalents per mole, depending on the conditions used. The difference in consumption of iodine by penicillin preparations before and after alkaline hydrolysis was found proportional to the quantity of the drug. Alicino found penicillin G consumed 8.97 equivalents of iodine per mole under the conditions used in his assay procedure. He later demonstrated 0 other deactivated penicillins, including phenoxymethyl penicillin, consume nine equivalents of iodine per mole while 6-amino-penicillanic acid consumes only eight equivalents of iodine per mole. 

In spite of usefulness of the simplification obtained by decreasing the experimental substrate concentration, many studies are aimed at the investigation of kinetic properties of immobilized biocatalysts within broader concentration ranges. In a previous paper [29], cells of Escherichia coli with penicillin acylase activity were immobilized by entrapment in calcium pectate gel and tested on the transformation of penicillin G to 6-amino penicillanic acid. Figure 9 shows experimental data from a microcalorimetric investigation of the penicillin G transformation in steady state. As appreciable particle-mass transfer was expected, the mathematical model that includes particle-mass balance was used. 

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... 

Production of fine chemicals. Inspite of the interest shown in the production of bulk chemicals in aqueous two-phase systems, the potential of these systems for fine chemical production has not yet been exploited. The only bioconversion reported has been the deacylation of benzyl penicillin to 6-amino penicillanic acid (15). Today, industrial deacylation is performed by penicillin acylase in an immobilized form. The productivity of the reaction in a... 

Scheme 19.18 Production of the semisynthetic penicillins. This process takes advantage of large-scale fermentation to obtain penicillin G (61) from microbes in order to establish the requisite stereochemistry at positions 3, 5, and 6 as indicated on 6-APA. An isolated enzyme (Penicillin Acylase) is then used to cleave the phenylacetic acid group off of the 6-position amide in 61. The resulting 6-amino-penicillanic acid (6-APA) can then be readily acylated with any acid chloride under buffered conditions so as to prevent a build-up in acidity during the reaction. Table 19.8 lists some representative semi-synthetic penicillins.

Production of 6-amino penicillanic acid (6-APA) from penicillin G or V by the action of penicillin amidase from E. coli, Bacillus megaterium, or Bovista plumba (Toyo Jozo Inc., Asahi Chemical Industry Co., Ltd., Fujisawa Pharmaceutical Co., Gist-Brocades/DSM, Novo-Nordisk, Pfizer, and others). Annual world production of 6-APA 6000 tons, used for the manufacture of semisynthetic penicillins. 

Molinari M, Schneider CH, de Week AL, Gruden E, Pfeuti C (1973) Ober pseudomonova-lente penicilloyl-kohlehydrate. Z Immun Forsch 146 225 Moller NE (1978) Carbenicillin-induced haemorrhagic cystitis. Lancet 2 946 Molthan L (1969) Reactions to cephalothins in patients with hemagglutinating penicillin antibodies. (Abstract). Ann Intern Med 70 1090 Moss MO (1964) Reaction of 6-amino penicillanic acid with frequentin. Experientia 20 605... 

Weston RD (1968) Penicilloylated protein contaminating 6-amino-penicillanic acid and benzylpenicillin. Antimicrob Agents Chemother 25 553 Wheeler AW (1971) A method for measuring different classes of human immunoglobulins specific for the penicilloyl group. Immunology 21 547 White JM, Brown DL, Hepner GW (1968) Penicillin-induced haemolytic anemia. Br Med J 3 26... 

Production of modified penicillins is based predominantly on penicillin G (semi-synthetic penicillin). Penicillin G is split with carrier-linked acylase enzymes into phenylacetic acid and 6-aminopenicillanic acid examples of enzyme sources for the penicillinacylase are Escherichia coli or Bacillus megaterium. 6-Amino-penicillanic acid may be converted into a large number of highly-effective semisynthetic penicillin antibiotics, such as amoxycillin, by the introduction of suitable side-chains. 

The role of p-lactam acylases in the manufacturing of semisynthetic cephalosporins and penicillins. In the left pathway, the production of 6-amino penicillanic acid (6-APA) from the fermentation product penicillin G is shown. In the right pathway, the production of 7-aminocephalosporanic acid (7-ACA) from the fermentation product cephalosporin-C is depicted... 

The widespread use of penicillin eventually led to a clinical problem of penicillin-resistant staphylococci and streptococci. Resistance for the most part involved the penicillin-destroying enzyme, penicillinase, which attacked the beta-lactam structure of the 6-amino-penicillanic acid nucleus (6-APA). 

The discovery that 6-aminopenicillanic acid was produced in fermentations with P. chrysogenum to which no side-chain precursor was added suggested that acylation of this compound might represent the final step in the biosynthesis of the penicilHns. Whether this is so still appears to be an open question. 6-Amino-penicillanic acid (II) is formed from benzylpenicilUn and other penicillins (though not from penicilHn N) by the action of enzymes which exist in a number of microorganisms, including P, chrysogenum (Murao, 1955 Erickson and Bennett, 1965). It may therefore be a product, rather than a precursor, of the penicillins. 

D-(-)-a-Amino-a-(4-hydroxyphenyl)acetamido]penicillanic acid and D-(-)-a-Amino-p-hydroxybenzyl penicillin. In some early literature amoxicillin was referred to as p-hydroxy ampicillin. 

---