Semi-synthetic antibiotics

Pimecrolimus (58 Elidel ) Ascomycin Macrolactum antibiotic Semi-synthetic NP Microbial Inflammatory skin diseases and atopic dermatitis Blocks T-cell activation 505-517... 

Zotarolimus (53 Endeavor stent) Sirolimus (33) Macrolide antibiotic Semi-synthetic NP Microbial Cardiovascular surgery Inhibits cell proliferation, preventing scar tissue formation and minimizes restenosis in angioplasty patients 467 74... 

Telavancin (28 Vibativ ) Vancomycin (27) Antibiotic Semi-synthetic NP Microbial Antibacterial Inhibits bacterial cell wall synhiesis 304-311... 

Everolimus (40 Afinitor ) Sirolimus (34) Macrolide antibiotic Semi-synthetic NP Microbial Anticancer Inhibits mTOR kinase activity 375-382... 

Another important enzymatic process in the production of 7-ADCA, for use in the production of semi-synthetic cephalosporins, is the hydrolysis of 7-aminocephalosporanic add (7-ACA) by the enzyme acetyl esterase. This process, again using immobilisation techniques, is illustrated in Figure 6.16. Hie deacylated product can be used, for example, as an intermediate in the production of the important oral cephalosporin cefuroxime. We will return to cephalosporin antibiotics later in this chapter. 

Also illustrated in Figure 6.17 there is another important antibiotic, amoxicillin. Both amoxicillin and ampiciilin can be made enzymatically or chemically. Although enzymes are available that can be applied very well for the conversion of 6-APA into a variety of semi-synthetic penicillins, economic reasons are still impeding large scale applications. 

Rasor and Tischer (1998) have brought out the advantages of enzyme immobilization. Examples of penicillin-G to 6-APA, hydrolysis of cephalospwrin C into 7-ACA, hydrolysis of isosorbide diacetate and hydrolysis of 5-(4-hydroxy phenyl) hydantom are cited. De Vroom (1998) has reported covalent attachment of penicillin acylase (EC 3.51.11) from E.Coli in a gelatine-based carrier to give a water insoluble catalyst assemblase which can be recycled many times, and is suitable for the production of semi-synthetic antibiotics in an aqueous environment. The enzyme can be applied both in a hydrolytic fashion and a synthetic fashion. 6-APA was produced from penicillin-G similarly, 7-ADCA was produced from desa acetoxycephalosporin G, a ring expansion product of penicillin G. 

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. 

The p-lactams, mainly penicillins and cephalosporins, are by production volume the most important class of antibiotics worldwide, enjoying wide applicability towards a range of infectious bacteria. Most of the key molecules are semi-synthetic products produced by chemical modification of fermentation products. Production of these molecules has contributed significantly to the development of large-scale microbial fermentation technology, and also of large-scale biocatalytic processing. 

Note again that the strained P-lactam ring is more susceptible to nucleophilic attack than the unstrained side-chain amide function. However, by increasing the steric bulk of the side-chain, the approach of a P-lactamase enzyme to the P-lactam ring is hindered in the semi-synthetic antibiotic, giving it more resistance to enzymic hydrolysis. 

Table 2. Natural and Semi-synthetic p-lactam Antibiotics...

Table 3. Natural and Semi-synthetic Antibiotics of Protein Biosynthesis Inhibition...

Penicillins refer to a family of both natural and semi-synthetic antibiotics. Although all exhibit a 6-aminopenicillanic acid core ring structure (Figure 1.15), they differ in the structure of their side-chains. Naturally produced penicillins include penicillins G and V. Semi-synthetic penicillins can be manufactured by enzymatic removal of a natural penicillin side-chain (using... 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

Tetracyclines are a family of antibiotics which display a characteristic 4-fused-core ring structure (Figure 1.16). They exhibit broad antimicrobial activity and induce their effect by inhibiting protein synthesis in sensitive microorganisms. Chlortetracycline was the first member of this family to be discovered (in 1948). Penicillin G and streptomycin were the only antibiotics in use at that time, and chlortetracycline was the first antibiotic employed therapeutically that retained its antimicrobial properties upon oral administration. Since then, a number of additional tetracyclines have been discovered (all produced by various strains of Streptomyces), and a variety of semi-synthetic derivatives have also been prepared (Table 1.18). 

Table 1.19. Some aminoglycoside antibiotics which have gained significant therapeutic application. Producer microorganisms are listed in brackets. In addition to naturally produced aminoglycosides, a number of semi-synthetic derivatives have also found medical application. Examples include amikacin, a semi-synthetic derivative of kanamycin and netilmicin, an N-ethyl derivative of sissomicin...

Rifabutin, a semi-synthetic derivative of rifamy-cin S, is a bactericidal antibiotic primarily used in the treatment of tuberculosis. Its effect is based on blocking the DNA-dependend RNA-polymerase of the bacteria. Rifabutin is used in the treatment of infections with Mycobacterium avium intracellulare. Rifabutin is well tolerated in patients with HIV-related tuberculosis, but patients with low CD4 cell counts have a high risk of treatment failure or relapse due to acquired rifamycin resistance. 

Production of semi-synthetic antibiotics is now a widely adopted and mature technology. 

D-p-Hydroxyphenylglycine is an important component of certain semi-synthetic antibiotics such as the semi-synthetic cephalosporins cefadroxil and cefatrizine and the semi-synthetic penicillin amoxicillin, with a combined world market in excess of 3 x 10 /a. Synthesis was possible from DL-5-monosubstituted hydantoins (cyclic ureides of amino acids) provided that a selective D-hydantoinase could be found, which would be competitive with chemical methods. 

Some of the products formed are functional ingredients in their own right, such as high fmctose syraps, cefuroxime etc. Others are intermediates that can be either freely traded, such as acrylamide as a pre-polymer and 6-APA and p-hydroxyphenylglycine as precursors of semi-synthetic antibiotics. Alternatively some intermediates tend to be used in-house by the company producing them such as fS)-2-chloropropanoate and L-tert-leucine. 

In part, all the breakthroughs mentioned depended on process modifications in enzyme isolation, in purification, and in immobilization as well as in handling precipitating product in an immobilized enzyme reactor system. These new processes involving PGA in several central roles result in shorter and more cost-effective routes to semi-synthetic /3-lactam antibiotics. 

Figure 7.35 Pen G acylase in the process to semi-synthetic /2-lactam antibiotics (Drauz, 2002).

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

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