Penicillins Penicillin V,

The most commonly used source of penicillin V acylase is the fungus Bovista plumbia. Incubation of phenoxymethyl penicillin (penicillin V) with this enzyme produces a yield of about 90-92% 6-APA. 

The natural penicillins, primarily G and V, have a relatively narrow spectrum. They act mostly on gram-positive organisms. The fact that proper selection of precursors could lead to new variations in the penicillin side chain offered the first source of synthetic penicillins. Penicillin V, derived from a phenoxy-acetic acid precursor, attracted clinical use because of its greater acid tolerance, which made it more useful in oral administration. Also, 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-aminopenicillanic acid nucleus (6-APA). Semisynthetic penicillins such as ampicillin and carbenicillin have a broader spectrum. Some, such as methicillin, orafi-cillin, and oxacillin, are resistant to penicillinase. In 1984, Beecham introduced Augmentin, which was the first combination formulation of a penicillin (amoxicillin) and a penicillinase inhibitor (clavulanic acid). Worldwide production of semisynthetic penicillins is currently around 10,000 tons/year, the major producers are Smith Kline Beecham, DSM, Pfizer, and Toyo Jozo. 

Penicillium chrysogenum on complex solid media, with the result that they were mixtures differing from one another in the identity of the side-chain moiety. When a sufficient supply of phenylacetic acid is present in liquid media, this is preferentially incorporated into the molecule to produce mainly benzylpenicillin (penicillin G in the old nomenclature). Use of phenoxyacetic acid instead leads to phenoxymethyl penicillin (penicillin V). More than two dozen different penicillins have been made in this way, but these two are the only ones that remain in clinical use. The bicyclic penicillin nucleus itself is prepared biosynthetically via a complex process from an acylated cysteinyl valyl peptide. The complete exclusion of side chain precursor acids from the medium produces the fundamental penicillin nucleus, 6-APA, but in poor yield. By itself, 6-APA has only very weak antibiotic activity, but when substituted on its primary amino group with a suitable... 

Pruess and Johnson (274) partially purified an enzyme from P. chrysogenum which catalysed acyl-transfer from a number of P -S]-penicillins (penicillins V, G, K, X and dihydro-F) to 6-APA. The side-chains of penicillin N, methyl penicillin and phenylpenicillin were not transferred by this enzyme. The enzyme showed no penicillin amidase activity i. e. no 6-APA was generated when penicillin and enzyme were mixed in the absence of added 6-APA. Other compounds, such as esters of glycine, could act as acyl acceptors but not efficiently as 6-APA. 

The fact that proper selection of precursors could lead to new variations in the penicillin side chain offered the first source of synthetic penicillins. Penicillin V, derived from a phenoxyacetic acid precursor, attracted clinical use because of its greater acid tolerance, which made it more useful in oral administration. 

Certain factors and product precursors are occasionally added to various fermentation media to iacrease product formation rates, the amount of product formed, or the type of product formed. Examples iaclude the addition of cobalt salts ia the vitamin fermentation, and phenylacetic acid and phenoxyacetic acid for the penicillin G (hen ylpenicillin) and penicillin V (phenoxymethylpenicillin) fermentations, respectively. Biotin is often added to the citric acid fermentation to enhance productivity and the addition of P-ionone vastly iacreases beta-carotene fermentation yields. Also, iaducers play an important role ia some enzyme production fermentations, and specific metaboHc inhibitors often block certain enzymatic steps that result in product accumulation. 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

At present all of the cephalosporins ate manufactured from one of four P-lactams, cephalosporin C (2), penicillin V [87-08-17, penicillin G [113-98-4] and cephamycin C (8), which ate all produced in commercial quantities by fermentation (87). The manufacturing process consists of three steps fermentation, isolation, and chemical modification. 

The only penicillins used in their natural form are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). The remainder of penicillins in clinical use are derived from 6-APA and most penicillins having useful biological properties have resulted from acylation of 6-APA using standard procedures. 

The pharmacology of penicillins differs markedly from compound to compound but has been well reviewed (57). The majority of derivatives, including penicillin G and the antipseudomonal penicillins, ate unstable in gastric acid and ate not available orally. The isoxazolyl penicillins ate relatively acid stable but not consistendy well absorbed by the oral route. Nafcillin and oxacillin ate poody absorbed orally cloxacillin, dicloxacillin, and ducloxacillin ate more teUable. Penicillin V, ampicillin, and patticulady amoxicillin ate relatively well absorbed orally. Esters of ampicillin such as bacampicillin, pivampicillin, and talampicillin improve the level of oral absorption of ampicillin to that achieved by amoxicillin. Absorption can be diminished by food after oral adruinistration, however, and peak blood levels, usually achieved after 1 to 2 h, ate somewhat delayed after ingestion of food. 

Table 2. Typical Operating Parameters for Immobilized Glucose Isomerase and Penicillin V Acylase...

Immobilized enzyme Glucose isomerase Penicillin V acylase... 

En2yme techniques are primarily developed for commercial reasons, and so information about immobilisation and process conditions is usually Limited. A commercially available immobilised penicillin V acylase is made by glutaraldehyde cross-linking of a cell homogenate. It can be used ia batch stirred tank or recycled packed-bed reactors with typical operating parameters as iadicated ia Table 2 (38). Further development may lead to the creation of acylases and processes that can also be used for attaching side chains by ensymatic synthesis. 

In an unusual application of the Wittig reaction, treatment of clavulanic acid derivatives and esters of penicillin V with methoxycarbonylmethylenetriphenylphosphorane afforded the corresponding exo-alkylideneazetidines. Thus penicillin V benzyl ester (104) gave (lOS) as a mixture of E and Z isomers. The /3-lactam could be regenerated by low-temperature ozonolysis (81CC929). 

The importance of the penicillins as a class of heterocyclic compounds derives primarily from their effectiveness in the treatment of bacterial infections in mammals (especially humans). It has been estimated that, in 1980, the worldwide production of antibiotics was 25 000 tons and, of this, approximately 17 000 tons were penicillins (81MI51103). The Food and Drug Administration has estimated that, in 1979 in the U.S.A., 30.1 x 10 prescriptions of penicillin V and 44.3 x 10 prescriptions of ampicillin/amoxicillin were dispensed. This level of usage indicates that, compared to other methods of dealing with bacterial infection, the cost-benefit properties of penicillin therapy are particularly favorable. Stated differently, penicillin treatment leads to the elimination of the pathogen in a relatively high percentage of cases of bacterial infection at a relatively low cost to the patient in terms of toxic reactions and financial resources. 

Penicillin V—see Penicillin, phenoxymethyl-, 7, 300 Penicilloate, benzyl-, 7, 303 Penicilloate, D-a-benzyl-a-methyl ester, 7, 303 Penillamine, benzyl-, 7, 303 Penillic acid, benzyl-, 7, 303 Penilloaldehyde, benzyl-, 7, 303 Penilloic acid, benzyl-, 7, 303 Penillonic acid, benzyl-methyl ester, 7, 303 1,2,3,4,6-Pentaazaindene nomenclature, 1, 18 Pentadeca-5,10-dienols synthesis, 1, 428 Pentadienol, tetrachloro-2H-pyran synthesis from, 3, 740 Pentadienonitrile, 5-(l,2-benzoselenazol-3-yl)-X-ray diffraction, 6, 334 Penta-2,4-dienonitrile, 5-(dimethylamino)-2-(2-thienyl)-... 

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

Following the realization that the presence of phenylacetic acid in the fermentation led to a simplification of the mixture of penicillins produced by the fungus due to preferential uptake of this acid and its incorporation into benzylpenicillin (4), a wide variety of other acids were added to the growing culture. Inclusion of the appropriate acids in the culture medium thus afforded, respectively, phenoxymethylpenicillin (5, penicillin V), phenethicillin propicillin (7), and phehbencillin... 

Approximately 1,000 g of phenoxymethylpenicillin acid (Penicillin V) is dissolved directly in about 5 liters of ethyl acetate to a concentration of 20% w/v. The resulting solution Is fil-... 

Epicillln Floxaclllin Methicillin sodium Nafcillin sodium Oxacillin sodium Penicillin V... 

Penicillin G hydrabamine Dehydroabietyl ethylene diamine Penicillin V hydrabamine 1 -Dehydro-6tt-methyl-9a-fluorohydro-cortisone Fluorometholone 6-Dehydro-17-methyltestosterone Calusterone... 

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