Biocatalytic Synthesis of β‐lactam Antibiotics

Deaguero, Andria L.; Blum, Janna K.; Bommarius, Andreas S.

doi:10.1002/9780470054581.eib640

Cited by 9 publications

(4 citation statements)

References 117 publications

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“…β-Lactam antibiotics can be manufactured using the enzymatic synthesis by penicillin G acylase . This enzyme catalyzes the reaction of phenylglycine methyl ester (D-PGME) and 6-aminopenicillanic acid (6-APA) to form ampicillin.…”

Section: Introductionmentioning

confidence: 99%

Crystallization Kinetics of Ampicillin Using Online Monitoring Tools and Robust Parameter Estimation

Encarnación-Gómez

Bommarius

Rousseau

2016

Ind. Eng. Chem. Res.

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Crystallization kinetics of ampicillin were estimated from induction-times and seeded and unseeded experiments. The concentration of ampicillin in solution was monitored by polarimetry and refractometry, while crystals were analyzed by focused beam refractive measurements and light microscopy. Variations of solute concentration with time, along with measured induction times were used to estimate parameters in kinetic expressions for primary nucleation, secondary nucleation, and crystal growth rate. Experimental data were obtained in runs involving different rates of change of pH, mass of seed crystals, and initial supersaturation. These data were used in parameter-estimation routines consisting of a stochastic minimization to localize a set of parameters spanning all the experiments, followed by a deterministic minimization to refine the parameters. The result was a set of parameters that fit a range of conditions of seeded and unseeded crystallizations and gave good estimates of desupersaturation rates.

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Section: Introductionmentioning

confidence: 99%

Crystallization Kinetics of Ampicillin Using Online Monitoring Tools and Robust Parameter Estimation

Encarnación-Gómez

Bommarius

Rousseau

2016

Ind. Eng. Chem. Res.

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“…[20] In our experiments, we targeted a D -PGME/6-APA ratio of 60 m M :20 m M which has been demonstrated as the optimal ratio for both iPGA[21] and AEH-catalyzed syntheses. [6]…”

Section: Resultsmentioning

confidence: 99%

“…Additional experiments were conducted in which pH was controlled between 7.0±0.1; the pH control had no effect on the results of the experiment. In reactions where iPGA was used in both steps, we replaced the AEH with equivalent AMP synthesis units of iPGA based on initial synthesis rate data from 6-APA and D -PGME using only AEH[6] and only iPGA[21] where 1 UAmp of AEH≈1 UAmp of iPGA≈6.8 UPenG of iPGA.…”

Section: Methodsmentioning

confidence: 99%

Ampicillin Synthesis Using a Two‐Enzyme Cascade with Both α‐Amino Ester Hydrolase and Penicillin G Acylase

Blum¹,

Deaguero²,

Pérez³

et al. 2010

ChemCatChem

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The current enzymatic production of semisynthetic β-lactam antibiotics requires isolation and purification of the intermediate 6-aminopenicillanic acid which adds cost and complexity to the manufacturing process. In this work, we took advantage of the unique substrate specificity of aamino ester hydrolases to perform a purely aqueous one-pot production of ampicillin from penicillin G and D-phenylglycine methyl ester, catalyzed by α-amino ester hydrolase and penicillin G acylase. The synthesis was performed in both a one-pot, one-step synthesis resulting in a maximum conversion of 39%, and a one-pot, two-step process resulting in a maximum conversion of 47%. The two-enzyme cascade reported in this paper is a promising alternative to the current enzymatic two-step, two-pot manufacturing process for semisynthetic β-lactam antibiotics which requires intermittent isolation of 6-aminopenicillanic acid.

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“…To achieve this, at the first stage, cephalosporin nucleus or 7-aminocephalosporanic acid (7-ACA) is obtained in vitro from CefC, either chemically or enzymatically (using D-amino acid oxidase (EC 1.4.3.3) and glutaryl-7aminocephalosporanic acid acylase (EC 3.5.1.93)) [56,198,199]. The side groups of 7-ACA are then modified by various chemical or enzymatic methods to produce cephalosporin drugs [56,169,200,201].…”

Section: Fermentation Of a Chrysogenum For Cephalosporin C (Cefc) Pro...mentioning

confidence: 99%

Industrial Production of Antibiotics in Fungi: Current State, Deciphering the Molecular Basis of Classical Strain Improvement and Increasing the Production of High-Yielding Strains by the Addition of Low-Molecular Weight Inducers

Zhgun

2023

Fermentation

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The natural fermentation of antibiotics, along with semi-synthetic and synthetic approaches, is one of the most important methods for their production. The majority of the antibiotic market comes from the fermentation of high-yielding (HY) fungal strains. These strains have been obtained since the 1950s from wild-type (WT) isolates as a result of classical strain improvement (CSI) programs primarily involving multi-round random mutagenesis and screening. However, the molecular basis leading to high-yield production was unknown. In recent years, due to the application of multiomic approaches, key changes that occur in CSI programs, with WT strains that become HY industrial producers of a particular antibiotic, have begun to be understood. It becomes obvious that, during CSI, certain universal events are selected, which lead both to a direct increase in the production of the target metabolite and affect other vital processes of the cell (side mutations). These key events include: the upregulation of the target biosynthetic gene cluster (BGC), changes in the system of global regulation, disruption of alternative BGCs, the rearrangement of energy fluxes in favor of the target SM (secondary metabolite), changes in the regulation of the response to stress, and the redirection of primary metabolic pathways to obtain more precursors for target production. This knowledge opens up the possibility of both introducing targeted changes using genetic engineering methods when creating new producers and increasing the production of CSI strains as a result of fermentation with low-molecular compounds, targeted to compensate for the effects of side mutations.

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Biocatalytic Synthesis of β‐lactam Antibiotics

Cited by 9 publications

References 117 publications

Crystallization Kinetics of Ampicillin Using Online Monitoring Tools and Robust Parameter Estimation

Crystallization Kinetics of Ampicillin Using Online Monitoring Tools and Robust Parameter Estimation

Ampicillin Synthesis Using a Two‐Enzyme Cascade with Both α‐Amino Ester Hydrolase and Penicillin G Acylase

Industrial Production of Antibiotics in Fungi: Current State, Deciphering the Molecular Basis of Classical Strain Improvement and Increasing the Production of High-Yielding Strains by the Addition of Low-Molecular Weight Inducers

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