Study on genetic engineering of Acremonium chrysogenum , the cephalosporin C producer

Hu, Youjia; Zhu, Bo

doi:10.1016/j.synbio.2016.09.002

Cited by 33 publications

(21 citation statements)

References 77 publications

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“…Whenever possible, these defects may be identified and corrected using modern “omics” techniques, systems biology and synthetic biology approaches, metabolic modeling, genome editing, reverse genetics etc [ 68 , 69 ]. Successful examples of the application of this strategy towards metabolic engineering of industrial beta-lactam producing strains include overexpression of cefG gene [ 62 ], introduction of a truncated gene copy for PacC transcription factor, modulation of strain morphology through manipulation with Acatg1 [ 9 ] and Acthi1 [ 10 ] genes, enhancing oxygen uptake by expression of bacterial hemoglobin gene [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…These achievements, together with the development of methods for genetic manipulation and “omics” technologies applied to A . chrysogenum [ 16 , 17 ], opened new opportunities for improvement of industrial strains [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Several strategies of genetic manipulation can be used to enhance the level of the target secondary metabolites (SM) production or modify the important strains parameters such as productivity, product export, the concentration of by-products, stress-strain characteristics, morphology and so on [ 19 , 20 ]. Targets for such manipulation are transcription factors, transmembrane transporters, proteins that regulate secretion, signal transduction pathways, cell surface receptors, and enzymes of primary and secondary metabolism [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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The critical role of plasma membrane H+-ATPase activity in cephalosporin C biosynthesis of Acremonium chrysogenum

Zhgun¹,

Думина²,

Valiakhmetov

et al. 2020

PLoS ONE

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The filamentous fungus Acremonium chrysogenum is the main industrial producer of cephalosporin C (CPC), one of the major precursors for manufacturing of cephalosporin antibiotics. The plasma membrane H + -ATPase (PMA) plays a key role in numerous fungal physiological processes. Previously we observed a decrease of PMA activity in A . chrysogenum overproducing strain RNCM 408D (HY) as compared to the level the wild-type strain A . chrysogenum ATCC 11550. Here we report the relationship between PMA activity and CPC biosynthesis in A . chrysogenum strains. The elevation of PMA activity in HY strain through overexpression of PMA1 from Saccharomyces cerevisiae , under the control of the constitutive gpdA promoter from Aspergillus nidulans , results in a 1.2 to 10-fold decrease in CPC production, shift in beta-lactam intermediates content, and is accompanied by the decrease in cef genes expression in the fermentation process; the characteristic colony morphology on agar media is also changed. The level of PMA activity in A . chrysogenum HY OE :: PMA1 strains has been increased by 50–100%, up to the level observed in WT strain, and was interrelated with ATP consumption; the more PMA activity is elevated, the more ATP level is depleted. The reduced PMA activity in A . chrysogenum HY strain may be one of the selected events during classical strain improvement, aimed at elevating the ATP content available for CPC production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The critical role of plasma membrane H+-ATPase activity in cephalosporin C biosynthesis of Acremonium chrysogenum

Zhgun¹,

Думина²,

Valiakhmetov

et al. 2020

PLoS ONE

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“…Cephalosporin C was firstly identified as a metabolite of Cephalosporium acremonium in 1948. By 1959, 7-aminocephalosporanic acid (7-ACA) was obtained from its hydrolysis under acidic conditions, thereby introducing the precursor to a multitude of semi-synthetic cephalosporins [63]. Figure 2 exemplifies the evolution of semi-synthetic cephalosporins, their timeline of introduction and the pros and cons of the succeeding generations marketed so far.…”

Section: Onto the Medicinal Chemistry Era: Semi-synthesismentioning

confidence: 99%

Antibiotic Discovery: Where Have We Come from, Where Do We Go?

2019

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Given the increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures—platforms—that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines. During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

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“…The strain improvement programs of A. chrysogenum , P. chrysogenum, and T. reesei are suitable examples for the efficiency of classical strain improvement by random mutagenesis (Hu and Zhu 2016; Peterson and Nevalainen 2012). However, the random introduction of point mutations also has disadvantages.…”

Section: Strain Improvement Using Genomics and Functional Genomicsmentioning

confidence: 99%

Inducible promoters and functional genomic approaches for the genetic engineering of filamentous fungi

Kluge

Terfehr

Kück

2018

Appl Microbiol Biotechnol

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In industry, filamentous fungi have a prominent position as producers of economically relevant primary or secondary metabolites. Particularly, the advent of genetic engineering of filamentous fungi has led to a growing number of molecular tools to adopt filamentous fungi for biotechnical applications. Here, we summarize recent developments in fungal biology, where fungal host systems were genetically manipulated for optimal industrial applications. Firstly, available inducible promoter systems depending on carbon sources are mentioned together with various adaptations of the Tet-Off and Tet-On systems for use in different industrial fungal host systems. Subsequently, we summarize representative examples, where diverse expression systems were used for the production of heterologous products, including proteins from mammalian systems. In addition, the progressing usage of genomics and functional genomics data for strain improvement strategies are addressed, for the identification of biosynthesis genes and their related metabolic pathways. Functional genomic data are further used to decipher genomic differences between wild-type and high-production strains, in order to optimize endogenous metabolic pathways that lead to the synthesis of pharmaceutically relevant end products. Lastly, we discuss how molecular data sets can be used to modify products for optimized applications.

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Study on genetic engineering of Acremonium chrysogenum , the cephalosporin C producer

Cited by 33 publications

References 77 publications

The critical role of plasma membrane H+-ATPase activity in cephalosporin C biosynthesis of Acremonium chrysogenum

The critical role of plasma membrane H+-ATPase activity in cephalosporin C biosynthesis of Acremonium chrysogenum

Antibiotic Discovery: Where Have We Come from, Where Do We Go?

Inducible promoters and functional genomic approaches for the genetic engineering of filamentous fungi

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