Semi-synthetic P-lactams

In our discussion of the diversification of the fMactams, we explained how acylases and acylating enzymes may be used in the production of modified (semi-synthetic) P-lactams. However, the potential of using enzymes to modify oiganic molecules is much wider than this. 

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

More recently, a biocatalytic manufacturing route was developed in which deacylation was accomplished by penicillin G acylase in water at room temperature, requiring no protection and deprotection (Scheme 8.9) [58]. Moreover, through reaction engineering, penicillin G acylase also catalyzes the acylation of 6-APA with either amino esters or aminoamides to produce a wide range of semi-synthetic P-lactam antibiotics such as amoxicillin and ampicillin. A similar approach could be applied to the synthesis of the 7-ADCA derivatives cefaclor, cephalexin, and cefadroxil. 

Adsorption is a simple and straightforward route for biocatalyst immobilization which offers unique advantages over soluble enzymes, such as enhanced activity, increased selectivity, improved stability and reusability. For example, Assemblase, the commercial name of immobilized pencillin-G acylase from E. coli, has been used by industry for manufacture of the semi-synthetic p-lactam antibiotic cephalexin. ... 

PenicilUn acylase Bacteria, mold p-Lactam piecirrsors for semi-synthetic p-lactam antibiotics... 

Chemical Versus Enzymatic Synthesis of Semi-Synthetic P-Lactam Antibiotics... 

In the relatively few years since the preparation of the previous volume in this series, the explosion of synthetic and clinical experimentation on the semi and totally synthetic antibacterial p-lactam antibiotics has continued, providing a rich body of literature from which to assemble this chapter. The search for utopiasporin, the perfect cephalosporin, continues. The improvements in. spectrum and clinical properties achieved to date, however, are largely incremental and have been achieved at the price of substantially higher costs to the patient. Nonetheless, these newer compounds are truly remarkable when compared with the properties of the fermentation-derived substances from which they have sprung. 

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. 

The cephalosporins are p-lactam antibiotics that are closely related both structurally (Figure 30.7) and functionally to the penicillins. Most cephalosporins are produced semi-synthetically by the chemical attachment of side chains to 7-aminocephalosporanic add. Cephalosporins and cephamydns have the same mode of action as the penidllins and are affected by the same resistance mechanisms, but they tend to be more resistant than the penidllins to p-lactamases. 

Since the discovery of the P-lactam antibiotic penicillin G (Fig. 12.2-3) by Fleming in 1929, the use of antibiotics against pathogenic bacteria has increased dramatically. Penicillin G was initially used, which must be applied intravenously because of its instability in the stomach, but now penicillin V, which can be administered orally, has been introduced. However, as a result of the increasing resistance of bacteria, new antibiotics had to be developed. The semi-synthetic antibiotics, which often possess a broad spectrum of antibacterial activity, were produced by altering the side chain of penicillin G through acylation of the amine function of 6-aminopenicillanic acid (6-APA)[56. ... 

Ceftiofur is a semi-synthetic antibiotic of the cephalosporin class. Cephalosporins, like penicillins, belong to the group of P-lactam antibiotics. 3-Lactams are probably the class of antibiotics most widely used in veterinary medicine for the treatment of bacterial infections of animals used in livestock farming and bovine milk production. There are EU MRLs for all food-producing species ranging from 4 pg/1 for ampicillin in milk to 300 pg/kg for oxacillin, cloxacillin, and dicloxacillin in bovine tissues such as... 

Bruggink A (2000), Green solutions for chemical challenges biocatalysis in the synthesis of semi-synthetic antibiotics. In Zwanenburg B, Mikolajczyk M, Kielbasinsky P (eds) Enzymes in action. NATO sciences series 1/33, Kluwer Academic, pp 449-458 Bruggink A, Roos EC, de Vroom E (1998) Penicillin acylase in the industrial production of lactam antibiotics.Org Process Res Dev2 128-133... 

Tramper, J., H. H. Beeftink, A. E. M. Janssen, L. P. Ooijkaas, J. L. van Roon, M. Strubel, and C. G. P. H. Schroen. 2001. Biocatalytic Production of Semi-Synthetic Cephalosporins Process Technology and Integration. In Synthesis of Beta-Lactam Antibiotics Chemistry, Biocatalysis and Process Integration, edited by A. Bruggink, 206-249. Springer-Verlag. 

A second major approach to semi-synthetic cephamycin synthesis utilises carbanion formation a to the P-lactam carbonyl. Reaction with electrophiles then provides substrates suitable for the introduction of the methoxy group. Several papers have described how the anion generated from the SchifPs base (220 =60 ) reacts readily with methyl methan-... 

The penicillins can be classified on the basis of their antibacterial activity (broad spectrum, narrow spectmm), method of production (natural or semi-synthetic) and based on their stability/instability to bacterial P-lactam ases. 

The cephamycins, a class of cephalosporins obtained from Streptomyces sp., display broad-spectrum antibacterial activity and stability to P-lactamases. The cephamycins contain a methoxyl substituent on the p-lactam ring and the shielding effect makes the ring less susceptible to lactamase attack. A clinically useful semi-synthetic analogue of cephamycin is Cefoxitin (Fig. 22.26). 

---