Industrial production of β-lactam antibiotics

  title={Industrial production of $\beta$-lactam antibiotics},
  author={Richard Paul Elander},
  journal={Applied Microbiology and Biotechnology},
  • R. Elander
  • Published 3 April 2003
  • Biology
  • Applied Microbiology and Biotechnology
The industrial production of β-lactam antibiotics by fermentation over the past 50 years is one of the outstanding examples of biotechnology. Today, the β-lactam antibiotics, particularly penicillins and cephalosporins, represent the world's major biotechnology products with worldwide dosage form sales of ~US$ 15 billion or ~65% of the total world market for antibiotics. Over the past five decades, major improvements in the productivity of the producer organisms, Penicillium chrysogenum and… 
Advances in Beta-Lactam Antibiotics
Modern aspects of the processes are discussed in the present review including genetics, molecular biology, metabolic engineering, genomics, and proteomics, including the confined manipulation of genetically modified organisms (GMOs).
Biosynthesis of active pharmaceuticals: β-lactam biosynthesis in filamentous fungi
The biochemical properties of the enzymes of β-lactam biosynthesis in P. chrysogenum and the role of peroxisomes in this process are described.
Biosynthetic concepts for the production of β‐lactam antibiotics in Penicillium chrysogenum
This review summarizes current knowledge on the results of this classical strain improvement process, and discusses avenues to improve β‐lactam biosynthesis and to exploit P. chrysogenum as an industrial host for the production of other antibiotics and peptide products.
Prelude to rational scale-up of penicillin production: a scale-down study
A mathematical model including the information from both computational fluid dynamics and chemical reaction dynamics will be established for the prediction of detailed information over the entire period of the fermentation process and thereby for the optimization of penicillin production, and subsequently also benefiting other fermentation products.
Biocatalytic Synthesis of β‐lactam Antibiotics
The penicillins, cephalosporins, carbapenems, and monobactams, make up the β-lactam family of antibiotics, and the original chemical synthesis processes utilized to make these compounds required subzero temperatures, hazardous chemicals for protecting groups, and large volumes of organic solvents, rendering them both environmentally harmful and economically taxing.
Biosynthesis of β-lactam nuclei in yeast.
Studies on the biosynthetic pathways of clavulanic acid and cephamycin C in Streptomyces clavuligerus
Structures of CAD in complex with the NADPH co-factor, and clavulanic acid, are described here, leading to a proposed reaction mechanism, and an increased understanding of how the enzyme is able to catalyse a reaction involving such a labile intermediate.


The β-lactam antibiotics: past, present, and future
The β-lactam group of compounds are the most successful example of natural product application and chemotherapy and continued efforts have resulted in the improvement of these compounds with respect to potency, breadth of spectrum, activity against resistant pathogens, stability and pharmacokinetic properties.
Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi
  • A. Brakhage
  • Biology
    Microbiology and Molecular Biology Reviews
  • 1998
A comparison with the regulatory mechanisms (regulatory proteins and DNA elements) involved in the regulation of genes of primary metabolism in lower eukaryotes is thus of great interest and can be expected to have a major impact on rational strain improvement programs.
Genetic engineering approach to reduce undesirable by-products in cephalosporin C fermentation
By genetically engineering strains for increased copy number of the expandase/hydroxylase gene, this work was able to reduce the level of DAOC present in the fermentation broth to 50% of the control.
Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties.
A new beta-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297, and subsequently determined to be a hitherto unrecognized species, is designated StrePTomyces cattleya (NRRL 8057).
Clavulanic Acid: a Beta-Lactamase-Inhibiting Beta-Lactam from Streptomyces clavuligerus
A novel β-lactamase inhibitor has been isolated from Streptomyces clavuligerus ATCC 27064 and given the nameClavulanic acid, which resembles the nucleus of a penicillin but differs in having no acylamino side chain, having oxygen instead of sulfur, and containing a β-hydroxyethylidine substituent in the oxazolidine ring.
Development of the cephalosporin C fermentation taking into account the instability of cephalosporin C
Although the cephalosporin C titer in a fermentation levels off at 160–170h, the total of C+X rises almost linearly up to 200h, which greatly influences attempts to improve the cepsporin strain by genetic manipulation, or the process by alterations in technology.
Use of Recombinant DNA to Improve Production of Cephalosporin C By Cephalosporium acremonium
A recombinant DNA-modified strain of the filamentous fungus Cephalosporium acremonium, strain LU4-79-6, produced more of the antibiotic cephalosporin C than a non-recombinant strain, strain 394-4,
Production of Cephalosporin Intermediates by Feeding Adipic Acid to Recombinant Penicillium chrysogenum Strains Expressing Ring Expansion Activity
A novel and efficient bioprocess for production of the cephalosporin intermediates, 7-aminocephalosporank acid (7-ACA) or 7-AMino deacetoxycephalOSporanic acid ( 7-ADCA) is demonstrated, proving that adipyl-6-APA is a substrate for either enzyme in vivo.
Cephamycins, a New Family of β-Lactam Antibiotics I. Production by Actinomycetes, Including Streptomyces lactamdurans sp. n
A number of actinomycetes isolated from soil were found to produce one or more members of a new family of antibiotics, the cephamycins, which are structurally related to cephalosporin C. The
Cefoxitin and cephamycins: microbiological studies.
The therapeutic effectiveness of cefoxitin in experimental infections in mice confirms the excellent characteristics of this semisynthetic cephamycin and indicates that it should be a very valuable agent for treatment of bacterial infections.