Naturally occurring penicillin

Historically, the development of penems is contemporary with that of the naturally occurring carbapenems and the direction of penem research has clearly been influenced by the stmctures of the closely related natural products. The origins of the two groups of compounds is, however, quite different. Unlike carbapenems, no penems have been found in nature. When first described (84,85) they were viewed as hybrid molecules combining stmctural features of penicillins and cephalosporins. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

As many natural and synthetic /3-lactams bear 3-acylamino substituents, the corresponding free amines or protected forms thereof are versatile synthetic intermediates. They may be prepared in several ways, for example by deacylation of the 7-amido group in naturally occurring penicillins by enzymic or chemical means. Chemical degradation usually involves conversion of the amide to a chloroimidate followed by cleavage with aqueous alcohols (75S547 p. 560, 78T1731 p. 1753). 

Naturally occurring. For example, those produced by fermentation of moulds such as Penicillium notatum and P. chrysogenum. The most important examples are benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). 

Penicillinacylase is used industrially to catalyze the hydrolytic removal of the side chain in naturally occurring penicillins such as benzylpenicillin (4.49) and phenoxymethylpenicillin (4.50). The nucleus 6-aminopenicillic acid (4.48) is then used as the starting material for the preparation of semisynthetic penicillins. Appropriate acylation of the 6-NH2 group leads to )3-lactamase-stable and broad-spectrum penicillins. 

This chapter covers only the chiral compounds that are cited in the literature by virtue of their optical activity. To keep the chapter to an acceptable length, a discussion of the stereochemical properties of sulfenamides showing axial chirality is omitted (17). Similarly, to limit the scope of the review, the chemistry of penicillin, cephalosporin sulfoxides and related compounds (14,18,19), steroidal sulfoxides (15,16), and other naturally occurring chiral sulfur compounds (4) is not discussed. For the same reason, only selected results are discussed and in some cases only references are given to recent papers and review articles on special topics. 

Clavulanic acid is produced by Streptomyces clavuligerus and is structurally related to penicillins. This naturally occurring compound is a specific and irreversible inhibitor of a wide range of bacterial -lactamases and, therefore, can enhance the activity of penicillins and cephalosporins against many resistant organisms. Potassium clavulanate can be administered both orally and perenter-ally in combination with antibiotics sensitive to the action of -lactamases. 

All of the naturally occurring monohactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of Ihe C-3 amide side chain led to many potent new compounds. 

Table 13.3 Naturally occurring and synthetic penicillins (Nayler, 1991).

As indicated in Table 33-2, penicillins can be classified according to their chemical background, spectrum of antibacterial activity, or pharmacokinetic features.56 The naturally occurring penicillins (penicillin G and... 

Penicillin, erythromycin, tetracycline, and cephalosporins are among the most widely used. Synthetic modifications of the naturally occurring antibiotic compounds have produced many variations that have the necessary clinical properties. 

Throughout his career Fleming was intensely interested in naturally occurring antibacterial substances, and penicillin was actually the second antibiotic that he discovered. In 1922 he described the antibacterial properties of lysozyme, a substance found in egg whites, mucus, and tears, which lysed, or dissolved, certain bacteria. Fleming found that lysozyme could turn a thick, milky white suspension of bacteria into a clear solution in a matter of seconds. 

Acetylenic thiophene 2.9, found in some species of higher plants, is one of the few naturally-occurring thiophenes. However, the thiophene ring is used in several important pharmaceutical products, such as the penicillin antibiotic 2.10. 

N, in a cell-free extract of Cephalosporium acremonium.154 Only the naturally occurring tripeptide with the LLD-configuration was utilized for biosynthesis, from which it is clear that L-valine is built into the tripeptide with inversion of configuration and that later formation of penicillin N involves an epimerization in the a-aminoadipyl moiety. Although in these experiments only the valine fragment of the precursor was labelled, intact incorporation is indicated by the failure of L-cysteinyl-D-valine or 6-aminopenicillanic acid (160) to act as penicillin precursors, and by the observation that the formation of labelled valine could not be detected in the feeding experiment with (159). 

Many advances in organic chemistry involve making and using derivatives of carboxylic acids. Proteins are bonded by amide functional groups, and chemists have created synthetic amides that emulate the desirable properties of proteins. For example, the nylon in a climbing rope is a synthetic polyamide that emulates the protein in a spider s web. All the penicillin and cephalosporin antibiotics are amides that extend the antimicrobial properties of naturally occurring antibiotics. 

It is interesting that a number of slightly different penicillins are formed in nature by different strains of the mold. The formula in Table 30-2 represents benzyl penicillin (penicillin G), which is the product that is now manufactured and used. Other naturally occurring penicillins differ from benzyl penicillin only with respect to the part of the molecule that is shown on the left side of the structure. In benzyl penicillin there is indicated a benzyl group, Q.H-,—, in this position. Penicillin K contains the normal heptyl group in this position, the hydrocarbon chain CH3CHXHXH0CH0CH0—. It is not so effective as penicillin G in the treatment of infections. Scores of other penicillins have been made and investigated. 

Resistance to penicillins and cephalosporins. Naturally occurring strains of Ps. aeruginosa show a high level of resistance to penicillins and cephalosporins with the exception of carbenicillin. In many instances. 

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