Penicillin polymers

In 1967 Batchelor et al. (1967) described the formation of a higher molecular weight substance in concentrated aqueous solutions of benzylpenicillin when they were left to stand for a short time at room temperature. The substance was shown 

Since these observations of Batchelor and co-workers, a large amount of work has been concerned with polymerization of penicillins and 6-APA and considerable knowledge of the chemical structure, rate and mechanism of formation, and the immunologic properties of penicillin polymers has been obtained. 

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Table 1. Penicilloyl-specific antigenicity and amounts of penicillin polymers formed in aqueous solutions of some penicillins after standing for 14 days at room temperature. (Smith et al. 1971)...

In summary, it seems firmly established that penicillin polymers, and especially polymers formed from aminopenicillins, exhibit a strong penicilloyl-specific antigenicity and it is likely that they may play a part in the elicitation of some clinical allergic reactions to penicillin preparations. The question of immunogenicity of penicillin polymers is still to be fully resolved. 

Because of the immunologic effects of penicillin polymers which are strongly supposed to be of clinical importance, their presence in clinically used penicillin preparations should be controlled and kept at the lowest possible level. 

De Week AL, Schneider H (1980) Allergic and immunological aspects of therapy with ce-fotaxine and other cephalosporins. J Antimicrob Chemother 6 161 De Week AL, Schneider CH, Gutersohn J (1968) The role of penicilloylated protein impurities, penicillin polymers and dimers in penicillin allergy. Int Arch Allergy Appl Immunol 33 535... 

It is only necessary to postulate rapid mechanisms of extensive substitution of some in vivo carriers by BPO groups in order to explain the prompt elicitation of anaphylactic reactions by penicillins in hypersensitive humans or animals. In this case, however, it appears more likely that the reactions may be elicited by penicillin polymers (see Sect. 1.8). 

Directions for preparing a potentiometric biosensor for penicillin are provided in this experiment. The enzyme penicillinase is immobilized in a polyacrylamide polymer formed on the surface of a glass pH electrode. The electrode shows a linear response to penicillin G over a concentration range of 10 M to 10 M. 

A typical penicillin broth contains 20-35 mg/1 of antibiotic. Filtration is used to remove mycelial biomass from fermentation broth. The filtration may be subjected to filter aided polymers. Neutralisation of penicillin at pH 2-3 is required. Amyl acetate or butyl acetate is used as an organic solvent to remove most of the product from the fermentation broth. Finally, penicillin is removed as sodium penicillin and precipitated by a butanol-water mixture. 

Penicillin has an interesting mode of action it prevents the cross-linking of small peptide chains in peptidoglycan, the main cell wall polymer of bacteria. Pre-existing cells are unaffected, but all newly produced cells are abnormally grown. The newborn cells are unable to maintain their wall rigidity, and they are susceptible to osmotic lysis. 

Recommended model particle systems are enzymes immobilised on carriers ([27,44,45,47,49]), oil/water/surfactant or solvent/water/surfactant emulsions ([27, 44, 45] or [71, 72]) and a certain clay/polymer floccular system ([27, 42-52]), which have proved suitable in numerous tests. The enzyme resin described in [27,44,47] (acylase immobilised on an ion-exchanger) is used on an industrial scale for the cleavage of Penicillin G and is therefore also a biological material system. In Table 3 are given some data to model particle systems. 

The use of biocides is spread across the whole polymer range, e.g., paints, ropes, textiles, fibres, etc. Many are copper, silver or arsenic compounds and also various heterocyclic compounds, e.g., isothiazolines (which have some structural resemblance to penicillin). 

Another example from the "bio-world" is the production of micro-organisms for optimum product yield and quality. An example could be micro-organisms for the production of penicillin, whereas recently there have been developments to explore routes to produce monomers for synthetic polymers by means of micro-organisms. Diversity in the micro-organisms to be tested can be achieved either by genetic engineering or by random mutagenesis. 

Tor [7] developed a new method for the preparation of thin, uniform, self-mounted enzyme membrane, directly coating the surface of glass pH electrodes. The enzyme was dissolved in a solution containing synthetic prepolymers. The electrode was dipped in the solution, dried, and drained carefully. The backbone polymer was then cross-linked under controlled conditions to generate a thin enzyme membrane. The method was demonstrated and characterized by the determination of acetylcholine by an acetylcholine esterase electrode, urea by a urease electrode, and penicillin G by a penicillinase electrode. Linear response in a wide range of substrate concentrations and high storage and operational stability were recorded for all the enzymes tested. 

An interesting example of MIP-LC analytics was presented in a paper, which focused on the separation of antibiotics of similar structures. Columns are (commercially) available to separate penicillins ( 3-lactams) from other antibiotics. However, if the quantification of each of the 3-lactam compounds is required, a more selective stationary phase has to be found. Molecular imprinting allows the fabrication of phases specifically for each 3-lactam. If for instance the concentration of the P-lactam oxacillin in a food sample has to be selectively determined, a polymer imprinted with oxacillin is the right choice. Compared to a standard stationary phase, which only allowed the separation of the entire group of (5-lactams from other non-(3-lactam analytes (e. g., bacitracin), the MIP enables the separation of the imprinted species from the pair of non-imprinted 3-lactams penicillin V and penicillin G see Fig. 6 [29,30]. 

Fig. 6. A Chromatogram of a mixture containing the print molecule (oxacillin), two other p-lactam-antibiotics (penicillin G and penicillin V) and a non- 3-lactam-antibiotic (bacitracin) on an oxacillin imprinted MIP containing 4-vinylpyridine residues, cross-linked with TRIM. The analysis was performed in organic mobile phase (ACN/AcOH,99 l).B Same conditions but using the respective non-imprinted control polymer. C Structures of penicillin V, penicillin G, and oxacillin. Reprinted with permission from Skudar K, Briiggemann O, Wittelsberger A, Ramstrom O (1999) Anal Commun 36 327. Copyright 1999 The Royal Society of Chemistry...

H. Bundgaard, C. Larsen, Polymerization of Penicillins. IV. Separation, Isolation and Characterization of Ampicillin Polymers Formed in Aqueous Solution , J. Chromatogr. 1977, 132, 51-59. 

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