Antibiotics production, penicillin

There is only one choice for the antibiotic production process the synthesis of benzyl-penicillin (penicillin G, originally known as penicillin ). This, the most renowned antibiotic and the first one have been manufactured in bulk, is still universally prescribed.5 Although originally made by surface liquid culture, penicillin G is now produced by air-lift fermentation under aerated conditions. 

The manufacture of benzylpenicillin (penieillin G, originally just penicillin ) is chosen as a model for the antibiotic production process. It is the most renowned of antibioties and is the first to have been manufactured in bulk. It is still universally prescribed and is also in demand as input material for semisynthetic antibiotics (Chapter 5). Developments associated with the penicillin fermentation process have been a significant factor in the development of modem bioteehnology. It was a further 30 years, i.e. not until the 1970s, before there were signifieant new advances in industrial fermentations. 

The growth phase passes rapidly into the antibiotic-production phase. The optimum pH and temperature for growth are not those for penicillin production and there may be changes in the control of these parameters. The only other event that marks the onset of the production phase is the addition ofphenylacetic acid (PAA) by continuous feed. 

The advisability of using certain antibiotics, particularly penicillin and tetracycline, in animal feeds has been questioned because of their use in human medicine. Any use of an antibiotic that is prescribed for humans presents some risks to human health, whether the use is for humans, animals or for other purposes but. the uses also have benefits. Otherwise, they would not persist. Antibiotics are used in animal feeds to increase animal weight, increase efficiency of feed utilization, increase reproductive efficiency and decrease morbidity and mortality. These benefits to animals and animal producers are reflected in decreases in food costs to humans. There are also benefits to human health from use of antibiotics in food animals. By reducing the incidence of animal health problems, use of antibiotics in food animals reduce the transference of animal infections to humans. The contention that the effectiveness of penicillin and tetracycline for use in human medicine is rapidly diminishing as a result of the proliferation of resistant bacteria caused by subtherapeutic use of antibiotics in animal production is not supported by experimental data. Rather, the evidence suggests that a fairly stable level of resistance of the intestinal bacteria in humans has long since been established to penicillin and tetracycline as it has been in animals. 

Three broad groupings, of the antibiotic substances presently used in animal production, include (a) broad-spectrum antibiotics, including penicillins and tetracyclines, which are effective against a wide variety of pathogenic and non-pathogenic bacteria (b) several narrow-spectrum antibiotics that are not used in human medicine and. (c) the ionophore antibiotics, monensin. lasalocid and salinomycin Monensin and lasalocid are used as rumen fermentation regulators in beef cattle, and the three ionophores are used as coccidiostats in poultry production. The ionophores. which are not used in human medicine, were first introduced in the 1970 s and account for most of the increase in antibiotic usage in animal production since the 1960 s. 

Secondary metabolism is commonly achieved by uncoupling the anabolic from the growth pathways. The subsequent overflow metabolites are then channelled towards secondary products which may include such antibiotics as penicillin, tetracyclin and streptomycin. Figure 5.16 shows the relationship between secondary products and central anabolic pathways. 

The spectacular success of penicillin as a chemotherapeutic agent has led to the search for other antibiotic products of living organisms. Streptomycin, which is produced by the mold Actinomyces griseus, has been found to be valuable in the tupatrnent of diseases that are not effectively controlled by penicillin, and some other bacteriostatic agents also have been found to have significant value. 

We will begin by giving a brief overview of foe strategies that may be employed to produce desirable antibiotics. Then we will give a brief review of the history of the production of penicillin. We will foen examine foe mode of action of P-lactam antibiotics and briefly describe foe biosynthetic pathways of P-lactam antibiotic production. Subsequently we will examine, in greater depth, the biotransformation of penicillins. A consideration of cephalsporin production will follow and will be ccMnpared with foe production and diversification of penicillins. In foe final part of this chapter we will briefly describe foe new P-lactams. 

As a result of the build-up of antibiotic resistance, the demand for derivatives from penicillins and cephalosporins rather than for the natural fermentation products has increased. One of the problems in the manufacture of semi-synthetic penicillins and cephalosporins is that fhese are vulnerable compounds and chemical modification is elaborate and difficult. Modification of fhe initial fermentation products penicillin G/V and cephalosporin G by the use of enzymes has provided economically feasible routes to semi-synthetic penicillins and cephalosporins [31]. 

These approaches, developments, and states in industrial strain improvement and pathway characterization will be illustrated for some of the best characterized organisms, namely the two fungal species mainly employed in industrial [3-lactam antibiotic production, the penicillin producing Peni-cillium chrysogenum, and the cephalosporin C producer Acremonium chrysogenum. 

Table 6.2.1 Conversion Yield (Y) and Productivity (Pr) of Enzymatic Synthesis of 3-Lactam Antibiotics with Penicillin Acylase (PA) at Increasing Substrates Concentrations...

The setting up of new biotechnology companies (Section 1.4.2) was the key event for the development of biopharmaceuticals based on recombinant technologies. Antibiotic manufacture had been established before this (Section 1.3). Antibiotics are still the most important strategy against bacterial infections. The world production of antibiotics is estimated at over 60000 tons per aimum, valued at more than 30 billion per year [128, 129]. For the synthesis of semisynthetic penicUlins and cephalosporins, the fermentation products penicillin G and cephalosporin, respectively, are hydrolyzed by immobilized enzymes to yield the acid form with the intact P-lactam ring as the active principal 6-APA, 7-ACA, or 7-aminodeacetoxy cephalosporanic acid (7-ADCA). 

HF Antibiotic production from benzyl-penicUlin using penicillin amidase [200]... 

One of the most important groups of secondary products used in the treatment of diseases are the antibiotics (E 5.2) of which some 100 products are on the market. In 1980 worldwide antibiotic production was estimated at about 25,000 tons, including 17,000 tons of penicillins (D 23.3), 5,000 tons of tetracyclines (D 3.3.7), 1,200 tons of cephalosporins (D 23.3) and 800 tons of erythromycins (D 4). The search for new antibiotics continues because of the development of new resistant strains and the need for cheaper, safer, and more active products. Chemical modification of natural antibiotics is of increasing significance in this respect. Antibiotics are not only used in human or veterinary medicine, but on a large scale also for growth promotion of farm animals. 

With the demonstration of the chnical importance of penicillin, work on the antibiotics entered a new phase. The pharmaceutical industry used its large resources to screen many thousands of micro-organisms for antibiotic production. Methods were developed for producing antibiotics in deep aerated... 

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