Improvement of amphotericin B production by a newly isolated <i>Streptomyces nodosus</i> mutant

Zhang, Bo; Zhang, Haidong; Zhou, Yi-Teng; Huang, Kai; Liu, Zhi‐Qiang; Zheng, Yu‐Guo

doi:10.1002/bab.1579

Cited by 15 publications

(13 citation statements)

References 23 publications

(26 reference statements)

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“…S. nodosus ZJB2016050 (CCTCC M2017426, China Center for Type Culture Collection, Wuhan, China) was screened as a high amphotericin B production strain in our lab, which was used in this study (Zhang et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

“…Due to the medicinal value and the clinical importance described above, related researches on amphotericin B and its derivatives are more in-depth and mature. Concurrently, many classical breeding methods of high-yield strains including fermentation development (Siddique et al, 2014 ; Ahsan et al, 2017 ; Ju et al, 2017 ; Zhao et al, 2017 ) and efficient bioprocesses (Santos-Aberturas et al, 2011 ; Yao et al, 2018 ) have been applied to increase the titer of several polyene macrolide antibiotics (Pereira et al, 2008 ; Zhang et al, 2017 ). Another important strategy was reported, such that short-chain fatty acid, lower alcohols, and some salt substances can be added as precursors of macrolide antibiotics to derive a high product titer (Jing et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced AmB Production in Streptomyces nodosus by Fermentation Regulation and Rational Combined Feeding Strategy

Zhang

Chen

et al. 2020

Front. Bioeng. Biotechnol.

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Amphotericin B is a clinically important polyene macrolide antibiotic with a broad-spectrum antifungal activity. In this work, the addition of key precursors and differential metabolites, combined with staged fermentation process control strategies, was carried out to improve AmB production. Rationally designed addition strategies were proposed as follows: 4 mg/L isopropanol, 1 mM alanine, 1 g/L pyruvate, and 0.025 g/L nicotinamide were supplemented at 24 h. The AmB titer was ultimately enhanced to 6.63 g/L, with 28.5% increase in shake flasks fermentation. To further promote the biosynthesis of AmB, different glucose feeding strategies were investigated and the highest AmB titer (15.78 g/L) was obtained by constant speed fed-batch fermentation in a 5-L fermentor. Subsequently, compared with the batch fermentation (9.89 g/L), a novel combined feeding strategy was ultimately developed to improve the production of AmB by 85.9%, reaching 18.39 g/L that is the highest titer of AmB ever reported so far, in which the optimized components were fed at 24 h and the staged fermentation regulation strategies were used simultaneously. Moreover, the ratio of co-metabolite AmA decreased by 32.3%, from 3.1 to 2.1%. Through the detection of extracellular organic acids, the changes in α-ketoglutaric acid, pyruvate, and citric acid concentrations were identified as the most flexible metabolite nodes to further clarify the potential mechanism under different fermentation regulation strategies. These results demonstrated that the strategies above may provide new guidance for the industrial-scale production of AmB.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced AmB Production in Streptomyces nodosus by Fermentation Regulation and Rational Combined Feeding Strategy

Zhang

Chen

et al. 2020

Front. Bioeng. Biotechnol.

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“…Recently, Zhang and co-workers set out to improve yields of amphotericin B in a newly isolated strain Streptomyces spp. ZJB 2013082, which produced the antifungal substance in low yields [319]. Using a combination of ultraviolet (UV) and NTG mutagenesis, the mutant strain N3 was isolated, which produced 1735 mg/L, a substantially increased amount of the product compared to the 56.2 mg/L obtained from the parent strain ZJB 2013082.…”

Section: Amphotericin Bmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

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“…Bacterial Strains, Medium, and Culture S. nodosus ATCC 14899 (S. nodosus ZJB20130827) was isolated from soil sample. AmB high-yield mutagenic S. nodosus ZJB2016050 (S. nodosus N3) was obtained by NTG-UV treatment using an S. nodosus ATCC 14899 spore (Zhang et al, 2018). S. nodosus strains were cultured in a liquid GYM (glucose yeast extract-malt extract) medium and on a GYM agar medium for culture and sporulation, respectively.…”

Section: Methodsmentioning

confidence: 99%

Comparative Transcriptome Analysis of Streptomyces nodosus Mutant With a High-Yield Amphotericin B

Huang

Zhang

Chen

et al. 2021

Front. Bioeng. Biotechnol.

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Antibiotics play an important role in human health. Most antibiotics are derived from microbial secondary metabolites. Amphotericin is a polyene macrolide antibiotic synthesized by Streptomyces nodosus. S. nodosus ZJB2016050 with high-yield amphotericin B (AmB) was obtained by traditional mutagenesis using S. nodosus ATCC14899 as the original strain. The differences in the characterization of the two strains were found in color, mycelium morphology, and AmB yield. Subsequent comparative transcriptome explained the yield differences between the two strains. Pathways including the carbohydrate metabolic pathway and the secondary product synthesis pathway were targeted. The upregulation of glucokinase, phosphoglycerate mutase, and pyruvate dehydrogenase accelerates the consumption of glucose and has great effects on the accumulation of precursors. One of the competitive secondary metabolites of the polyketone synthetase (PKS) II type sapromomycin analog synthesis gene cluster was downregulated, which competes for malonyl-CoA. Five PKS modules (except for the first module amphA) of the amphotericin synthetic gene cluster in the high-yielding strain were downregulated, which resulted in the total amphotericin A (AmA) and AmB of S. nodosus ZJB2016050 being less than that of the wild-type S. nodosus ATCC14899. Combined with gene differential expression in the pentose phosphate pathway and the reaction mechanism of the ER5 domain, the reason that S. nodosus ZJB2016050 preferred to synthesize AmB was probably related to intracellular reduction.

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Improvement of amphotericin B production by a newly isolated Streptomyces nodosus mutant

Cited by 15 publications

References 23 publications

Enhanced AmB Production in Streptomyces nodosus by Fermentation Regulation and Rational Combined Feeding Strategy

Enhanced AmB Production in Streptomyces nodosus by Fermentation Regulation and Rational Combined Feeding Strategy

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Comparative Transcriptome Analysis of Streptomyces nodosus Mutant With a High-Yield Amphotericin B

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