Chemically Defined Media for Antibiotic Production

Perlman, D.

doi:10.1111/j.1749-6632.1966.tb41199.x

Cited by 6 publications

(2 citation statements)

References 50 publications

(3 reference statements)

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“…The recognition of the therapeutic value of penicillin (9) led to intensive research to increase productivity. This research involved strain improvement as well as the extensive optimization of process conditions and growth media (5,50,52,57,59,66,69). Growth in complex media was found to promote the synthesis of a wide range of ␤-lactam antibiotics (8), including benzylpenicillin (now commonly known as penicillin G).…”

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confidence: 99%

Resolving Phenylalanine Metabolism Sheds Light on Natural Synthesis of Penicillin G in Penicillium chrysogenum

et al. 2012

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The industrial production of penicillin G by Penicillium chrysogenum requires the supplementation of the growth medium with the side chain precursor phenylacetate. The growth of P. chrysogenum with phenylalanine as the sole nitrogen source resulted in the extracellular production of phenylacetate and penicillin G. To analyze this natural pathway for penicillin G production, chemostat cultures were switched to [U-13 C]phenylalanine as the nitrogen source. The quantification and modeling of the dynamics of labeled metabolites indicated that phenylalanine was (i) incorporated in nascent protein, (ii) transaminated to phenylpyruvate and further converted by oxidation or by decarboxylation, and (iii) hydroxylated to tyrosine and subsequently metabolized via the homogentisate pathway. The involvement of the homogentisate pathway was supported by the comparative transcriptome analysis of P. chrysogenum cultures grown with phenylalanine and with (NH 4 ) 2 SO 4 as the nitrogen source. This transcriptome analysis also enabled the identification of two putative 2-oxo acid decarboxylase genes (Pc13g9300 and Pc18g01490). cDNAs of both genes were cloned and expressed in the 2-oxo-acid-decarboxylase-free Saccharomyces cerevisiae strain CEN.PK711-7C (pdc1 pdc5 pdc6⌬ aro10⌬ thi3⌬). The introduction of Pc13g09300 restored the growth of this S. cerevisiae mutant on glucose and phenylalanine, thereby demonstrating that Pc13g09300 encodes a dual-substrate pyruvate and phenylpyruvate decarboxylase, which plays a key role in an Ehrlich-type pathway for the production of phenylacetate in P. chrysogenum. These results provide a basis for the metabolic engineering of P. chrysogenum for the production of the penicillin G side chain precursor phenylacetate.

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Resolving Phenylalanine Metabolism Sheds Light on Natural Synthesis of Penicillin G in Penicillium chrysogenum

et al. 2012

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“…The imbalance between the natural product production potential of actinomycetes and the known compounds produced by these strains has resulted in a search for various methods to activate these "silent" clusters (Craney et al 2013). Many approaches, including alteration of media components (Perlman 1966), transformation of pleiotropic global regulators (McKenzie et al 2010), exposure to various compounds including inhibitors of fatty acid synthesis and known microbially produced inducers of antibiotic biosynthesis (Craney et al 2012), selection for mutants conferring antibiotic resistance (e.g., rifampin and streptomycin) (Wang et al 2008), and co-cultivation with other microbes (Watrous et al 2012;Traxler et al 2013), have been shown to alter the spectrum of natural product expression by actinomycetes. Combinations of these approaches can be systematically employed to activate biosynthetic gene clusters, thereby greatly enhancing the chemical diversity of compounds produced by microbes and possibly tapping into new chemical scaffolds suitable for antibiotic discovery.…”

Section: New Opportunities In Microbial Natural Product Discoverymentioning

confidence: 99%

Something old, something new: revisiting natural products in antibiotic drug discovery

2014

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Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an "apocalyptic" threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

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Microbial Synthesis of Cephalosporin and Penicillin Compounds

Lemke¹,

Brannon²

1972

Cephalosporins and Penicillins

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Chemically Defined Media for Antibiotic Production

Cited by 6 publications

References 50 publications

Resolving Phenylalanine Metabolism Sheds Light on Natural Synthesis of Penicillin G in Penicillium chrysogenum

Resolving Phenylalanine Metabolism Sheds Light on Natural Synthesis of Penicillin G in Penicillium chrysogenum

Something old, something new: revisiting natural products in antibiotic drug discovery

Microbial Synthesis of Cephalosporin and Penicillin Compounds

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