Synthesis of β-Lactam Antibiotics: Chemistry, Biocatalysis & Process Integration

Synthesis of ß-Lactam Antibiotics
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Its residues may easily meet strict environmental standards. However, the yield of enzymatic synthesis of ampicillin is lower than that of the chemical reaction.

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This work is an optimization study of the enzymatic synthesis of ampicillin, to identify process conditions under which this "green process" might become economically competitive. A thermodynamically controlled synthesis of the antibiotic, where the free amino acid phenylglicine, PG would be the acyl donor, is not favored. PGA from Escherichia coli requires that the PG carboxyl group should be protonated while, at the same time, the amino group of the b -lactam nucleus should be neutral, available for nucleophilic interactions Ospina et al.

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However, for the range of pHs where the enzyme is active pH , the number of substrate molecules having the reactive groups with the proper charge is negligible. The kinetically controlled synthesis of ampicillin is a strategy presented by several authors Cole, a; Kasche et al. In this strategy, PG is replaced by an activated substrate, such as an amide, ester, or anhydride. Kasche and Fernandez-Lafuente et al.

Two side reactions, also catalyzed by PGA, compete with the synthesis of ampicillin. PG and 6-APA are produced by the hydrolysis of ampicillin in series with the synthesis. Kasche reported that the antibiotic synthesis requires adsorption of 6-APA on the enzyme active site before the substrate-enzyme complex is formed. Ferreira et al.

Synthesis of β-Lactam Antibiotics

The rate of hydrolysis of ampicillin also decreased when PGME was present, but the inhibitory effects were very different in each case: the inhibitory effect of PGME on hydrolysis of ampicillin was much higher than that of ampicillin on hydrolysis of PGME. Consequently, productivity increased for higher concentrations of PGME, but the results of Ferreira et al.

The catalyst used in this work had the enzyme immobilized on agarose gel. Experimental conditions that eliminate mass transfer limitations for these reactions were previously investigated Ferreira et al. The enzymatic synthesis of ampicillin with PGA from E. For enzymatic synthesis of antibiotics in industrial reactors, it is essential that operational variables be set so that some performance parameters are maximized.

Each experimental variable of the reaction medium concentration of reactants, pH, temperature, solvents, etc. If the reaction variables are changed one at a time, around a central point, only part of the experimental domain is explored. Factorial design is a useful procedure that systematically changes the variables, simultaneously and in a suitable manner Barros Neto et al. The aim of this work was to find operational conditions that would simultaneously improve yield, selectivity, and productivity. All other chemicals were of laboratory grade from different commercial suppliers.

After each step, the gel was filtered and washed with distilled water. Colorimetric analysis of the 6-APA released during hydrolysis of penicillin G provided the basis for evaluation of enzyme activity. The difference between enzymatic activities of the supernatant free enzyme before and after immobilization was used to assess the enzymatic load of the gel.

Beta Lactam Antibiotics : Classification

A jacketed batch reactor with mechanical stirring was used in all the experiments. The amount of biocatalyst was constant in all assays 1. The pH of the solutions during the enzymatic synthesis reactions was controlled adding concentrated NaOH.

Biocatalyst engineering for the production of semi-synthetic antibiotics

Samples of 10 m l were taken from the reaction mixture, diluted in the mobile phase m l , and analyzed using HPLC. The variables studied were ones that could be easily used to define a cost- or profit-objective function for the process. Their definitions for a batch system follow: here N amp is the number of moles of ampicillin; is the number of moles of 6-APA at the beginning of the batch; is the maximum concentration of ampicillin, which is reached at time t max for each run; and img04 is the number of moles of undesired product phenylglycine.

Enzymatic synthesis assays were performed using a 2 5 factorial analysis.

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The experimental variables were temperature, pH, ionic strength, presence of organic solvent methanol , and substrate concentrations. The response variables are defined by equations 1 to 3. These variables and their ranges were selected based on several sources Boccu et al. A number of experimental variables may influence the enzymatic synthesis of b -lactam antibiotics.

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However, not all these variables exert a strong influence; thus, a screening was carried out using factorial analysis. The factorial planning is reported in Table 1. The experiments were carried out in a random sequence. The experimental results were treated according to Barros Neto et al. Coefficients of the responses yield, productivity, and selectivity and their cross interactions were estimated. The significance of these coefficients was evaluated using a standard deviation analysis.

Normal probability plots were used to discern significant effects, in accordance with Barros Neto et al. Figure 2 shows normal probability plots of the three responses yield, selectivity, and productivity. Effects in the middle of plots were "noise" with Gaussian distribution and zero mean. These coefficients reflected random fluctuations in the process.

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In this coupling reaction, two nucleophiles compete for cleavage of the acyl-enzyme intermediate: the nucleophile 6-APA, and water. Improved A. Penicillin G acylase, a gene encoding therefor and a method for the production of this enzyme. We successfully produce active AEH in E. Ghermes G.

The assays were not replicated. The significant effects were assumed to represent all responses satisfactorily, and the other ones were eventually used to estimate the standard deviation of the effects. Table 2 shows all effects on yield, productivity, and selectivity.

The response surfaces had thirty-two terms, including five-variable cross-interactions, but only the most significant effects were selected. Analysis of the normal probability plots indicated that the effects of methanol and ionic strength were not significant; these less significant effects for the three responses were used to estimate the standard error of the effects. The yield had s. The effect of pH, B in Table 2 , is the largest of all responses. The effect of methanol, C in Table 2 , is insignificant for all responses, but it must be considered when coupled with pH, BC effect in Table 2.

BC is positive for productivity and yield and negative for selectivity.

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Once again, a contradictory overall effect is present. When 6-APA concentration is low, high yields are achieved, but selectivity and productivity of the reaction decrease. It is important to stress that, in order to optimize the production of ampicillin economically all three responses must be taken into account. High productivity and yield are important, but selectivity must also be considered because PGME is hydrolyzed see Figure 1.

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