Biosynthetic process and strain improvement approaches for industrial penicillin production

2022 ◽  
Author(s):  
Amol M. Sawant ◽  
Koteswara Rao Vamkudoth
Keyword(s):  
Strain Improvement ◽  
Penicillin Production

scholarly journals Impact of Classical Strain Improvement of Penicillium rubens on Amino Acid Metabolism during β-Lactam Production

2019 ◽  
Vol 86 (3) ◽  
Author(s):  
Min Wu ◽  
Ciprian G. Crismaru ◽  
Oleksandr Salo ◽  
Roel A. L. Bovenberg ◽  
Arnold J. M. Driessen
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Strain Improvement ◽  
Tryptophan Synthase ◽  
Cysteine Biosynthesis ◽  
Penicillin Production ◽  
Content Type ◽  
Classical Strain ◽  
The Impact

ABSTRACT To produce high levels of β-lactams, the filamentous fungus Penicillium rubens (previously named Penicillium chrysogenum) has been subjected to an extensive classical strain improvement (CSI) program during the last few decades. This has led to the accumulation of many mutations that were spread over the genome. Detailed analysis reveals that several mutations targeted genes that encode enzymes involved in amino acid metabolism, in particular biosynthesis of l-cysteine, one of the amino acids used for β-lactam production. To examine the impact of the mutations on enzyme function, the respective genes with and without the mutations were cloned and expressed in Escherichia coli, purified, and enzymatically analyzed. Mutations severely impaired the activities of a threonine and serine deaminase, and this inactivates metabolic pathways that compete for l-cysteine biosynthesis. Tryptophan synthase, which converts l-serine into l-tryptophan, was inactivated by a mutation, whereas a mutation in 5-aminolevulinate synthase, which utilizes glycine, was without an effect. Importantly, CSI caused increased expression levels of a set of genes directly involved in cysteine biosynthesis. These results suggest that CSI has resulted in improved cysteine biosynthesis by the inactivation of the enzymatic conversions that directly compete for resources with the cysteine biosynthetic pathway, consistent with the notion that cysteine is a key component during penicillin production. IMPORTANCE Penicillium rubens is an important industrial producer of β-lactam antibiotics. High levels of penicillin production were enforced through extensive mutagenesis during a classical strain improvement (CSI) program over 70 years. Several mutations targeted amino acid metabolism and resulted in enhanced l-cysteine biosynthesis. This work provides a molecular explanation for the interrelation between secondary metabolite production and amino acid metabolism and how classical strain improvement has resulted in improved production strains.

scholarly journals Eighty Years after Its Discovery, Fleming's Penicillium Strain Discloses the Secret of Its Sex

2008 ◽  
Vol 7 (3) ◽  
pp. 465-470 ◽  
Author(s):  
Birgit Hoff ◽  
Stefanie Pöggeler ◽  
Ulrich Kück
Keyword(s):  
Antibacterial Activity ◽  
Sexual Reproduction ◽  
Strain Improvement ◽  
Mating Types ◽  
Penicillin Production ◽  
Industrial Strain ◽  
Pheromone Receptor ◽  
Improvement Programs ◽  
Alexander Fleming ◽  
Penicillium Strain

ABSTRACT Eighty years ago, Alexander Fleming discovered antibacterial activity in the asexual mold Penicillium, and the strain he studied later was replaced by an overproducing isolate still used for penicillin production today. Using a heterologous PCR approach, we show that these strains are of opposite mating types and that both have retained transcriptionally expressed pheromone and pheromone receptor genes required for sexual reproduction. This discovery extends options for industrial strain improvement programs using conventional genetical approaches.

scholarly journals Increased Penicillin Production in Penicillium chrysogenum Production Strains via Balanced Overexpression of Isopenicillin N Acyltransferase

2012 ◽  
Vol 78 (19) ◽  
pp. 7107-7113 ◽  
Author(s):  
Stefan S. Weber ◽  
Fabiola Polli ◽  
Rémon Boer ◽  
Roel A. L. Bovenberg ◽  
Arnold J. M. Driessen
Keyword(s):  
Penicillium Chrysogenum ◽  
Phenylacetic Acid ◽  
Strain Improvement ◽  
Single Copy ◽  
Limiting Factor ◽  
Penicillin Biosynthesis ◽  
Penicillin Production ◽  
Content Type ◽  
Coa Ligase ◽  
Isopenicillin N

ABSTRACTIntense classical strain improvement has yielded industrialPenicillium chrysogenumstrains that produce high titers of penicillin. These strains contain multiple copies of the penicillin biosynthesis cluster encoding the three key enzymes: δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine synthetase (ACVS), isopenicillin N synthase (IPNS), and isopenicillin N acyltransferase (IAT). The phenylacetic acid coenzyme A (CoA) ligase (PCL) gene encoding the enzyme responsible for the activation of the side chain precursor phenylacetic acid is localized elsewhere in the genome in a single copy. Since the protein level of IAT already saturates at low cluster copy numbers, IAT might catalyze a limiting step in high-yielding strains. Here, we show that penicillin production in high-yielding strains can be further improved by the overexpression of IAT while at very high levels of IAT the precursor 6-aminopenicillic acid (6-APA) accumulates. Overproduction of PCL only marginally stimulates penicillin production. These data demonstrate that in high-yielding strains IAT is the limiting factor and that this limitation can be alleviated by a balanced overproduction of this enzyme.

PENICILLIN PRODUCTION BY MUTANT OF Penicillium chrysogenum

2016 ◽  
Vol 2 (1) ◽  
pp. 15
Author(s):  
Dudi Hardianto ◽  
Suyanto . ◽  
Erwahyuni Endang Prabandari ◽  
Lira Windriawati ◽  
Edy Marwanta ◽  
...  
Keyword(s):  
Ultraviolet Irradiation ◽  
Penicillium Chrysogenum ◽  
Bacterial Infections ◽  
Strain Improvement ◽  
Penicillin Production ◽  
Wild Type ◽  
Random Mutation ◽  
Type Mutant ◽  
Physical And Chemical ◽  
Alexander Fleming

Penisilin adalah antibiotika yang pertama kali ditemukan dan digunakan untuk pengobatan infeksi bakteri. Sejak ditemukan penisilin sebagai antibiotika oleh Alexander Fleming pada tahun 1928, banyak usaha dilakukan untuk meningkatkan produktivitas Penicillium chrysogenum. Pemuliaan galur untuk meningkatkan produksi penisilin dapat menggunakan mutasi acak secara fisika dan kimia. Pada penelitian ini, radiasi sinar ultraviolet digunakan untuk mendapatkan mutan P. chrysogenum. Produksi penisilin ditentukan menggunakan HPLC dan produktivitas mutan dibandingkan dengan induk P. chrysogenum. Mutan M12 menghasilkan penisilin 1,23 kali lebih banyak dibandingkan dengan induk P. chrysogenum.Kata kunci: Penisilin, Penicillium chrysogenum, ultraviolet, mutan, radiasi ABSTRACTPenicillin is the first antibiotic discovered and used for treatment of bacterial infections. Since the discovery of penicillin as antibiotic by Alexander Fleming in 1928, much effort has been invested to improve productivity of Penicillium chrysogenum. Strain improvement to increase the penicillin production can be carried out by physical and chemical random mutation. In this research, ultraviolet irradiation was used to obtain P. chrysogenum mutant. Penicillin production was determined by using HPLC and productivity of P. chrysogenum mutants was compared to the wild type. Mutant M12 produced 1.23 fold higher penicillin than the wild type did.Keywords: Penicillin, Penicillium chrysogenum, ultraviolet, mutant, radiation

The History of Penicillin Production

1971 ◽  
Vol 12 (2) ◽  
pp. 355
Author(s):  
John Parascandola ◽  
Albert E. Elder
Keyword(s):  
Penicillin Production ◽  
History Of

scholarly journals Strain improvement ofPhaffia rhodozymaby protoplast fusion

1992 ◽  
Vol 93 (3) ◽  
pp. 221-226 ◽  
Author(s):  
Soon Bai Chun ◽  
Jong Eon Chin ◽  
Suk Bai ◽  
Gil-Hwan An
Keyword(s):  
Protoplast Fusion ◽  
Strain Improvement

Fresh approaches to antibiotic production

1980 ◽  
Vol 290 (1040) ◽  
pp. 313-328 ◽  
Keyword(s):  
Polyethylene Glycol ◽  
Plant Pathogens ◽  
Growth Promotion ◽  
Antibiotic Production ◽  
Strain Improvement ◽  
Antibiotic Biosynthesis ◽  
Yield Improvement ◽  
Acquired Drug Resistance ◽  
Intensive Farming ◽  
New Antibiotics

New antibiotics are needed, ( a ) to control diseases that are refractory to existing ones either because of intrinsic or acquired drug resistance of the pathogen or because inhibition of the disease is difficult, at present, without damaging the host (fungal and viral diseases, and tumours), ( b ) for the control of plant pathogens and of invertebrates such as helminths, insects, etc., and ( c ) for growth promotion in intensive farming. Numerous new antibiotics are still being obtained from wild microbes, especially actinomycetes. Chemical modification of existing compounds has also had notable success. Here we explore the uses, actual and potential, of genetics to generate new antibiotics and to satisfy the ever-present need to increase yield. Yield improvement has depended in the past on mutation and selection, combined with optimization of fermentation conditions. Progress would be greatly accelerated by screening random recombinants between divergent high-yielding strains. Strain improvement may also be possible by the introduction of extra copies of genes of which the products are rate-limiting, or of genes conferring beneficial growth characteristics. Although new antibiotics can be generated by mutation, either through disturbing known biosyntheses or by activating ‘silent’ genes, we see more promise in interspecific recombination between strains producing different secondary metabolites, generating producers of ‘hybrid’ antibiotics. As with proposals for yield improvement, there are two major strategies for obtaining interesting recombinants of this kind: random recombination between appropriate strains, or the deliberate movement of particular biosynthetic abilities between strains. The development of protoplast technology in actinomycetes, fungi and bacilli has been instrumental in bringing these idealized strategies to the horizon. Protoplasts of the same or different species can be induced to fuse by polyethylene glycol. At least in intraspecific fusion of streptomycetes, random and high frequency recombination follows. Protoplasts can also be used as recipients for isolated DNA, again in the presence of polyethylene glycol, so that the deliberate introduction of particular genes into production strains can be realistically envisaged. Various kinds of DNA cloning vectors are being developed to this end. Gene cloning techniques also offer rich possibilities for the analysis of the genetic control of antibiotic biosynthesis, knowledge of which is, at present, minimal. The information that should soon accrue can be expected to have profound effects on the application of genetics to industrial microbiology.

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