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Fermentation
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Pharmaceutical Fermentation: Antibiotic Production and Processing
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Pharmaceutical Fermentation: Antibiotic Production and Processing

A special issue of Fermentation (ISSN 2311-5637). This special issue belongs to the section "Fermentation Process Design".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 14496

Special Issue Editor

Dr. Alexander A. Zhgun

E-Mail Website
Guest Editor
Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, Russia
Interests: fungal biotechnology; antibiotic production; Acremonium chrysogenum; cephalosporin C; secondary metabolism; Aspergillus terreus; lovastatin; polyamines

Special Issue Information

Dear Colleagues,

The discovery of antibiotics led to a truly cardinal revolution in medicine, allowing humanity to effectively fight against numerous diseases. It is impossible to count how many human lives and how many people have been saved from suffering since the early 1950s thanks to the introduction of antibiotics into medical practice. The discovery of antibiotics is perhaps the most significant for humanity from a humanitarian point of view.

Currently, most antibiotics on the market are produced by fermentation as such (natural antibiotics), or using fermentation to obtain substrates for the further in vitro synthesis of antibiotics (semi-synthetic antibiotics). Over the past 70 years, since the early 1950s, the level of knowledge in the field of antibiotic fermentation has grown significantly. By classical methods (random mutagenesis and screening), numerous improved strains were created, and the level of antibiotic production was increased by 100–1000 or more times compared with natural isolates. Then, the means of genetic engineering, which appeared in the arsenal of scientists in the late 1980s, made it possible to carry out directed changes leading to the creation of industrial strains producing antibiotics. Modern technologies make it possible to change the pathways of biosynthesis in microorganism strains for the production of new antibiotics, effectively “awaken” orphan biosynthetic gene clusters (BGCs) for screening discovered natural products for antibiotic activity. At the current stage of scientific development, it is possible to obtain highly active antibiotic producers by combining classical methods and methods of recombinant technology, which are scaled up in industrial-scale fed-batch fermentation. For the easier perception of all this knowledge, it is important to summarize it in one thematic Special Issue.

In this regard, the goal of this Special Issue is to publish both recent innovative research results as well as review papers in the field of Pharmaceutical Fermentation: Antibiotic Production and Processing.

Potential topics include, but are not limited to:

  • Screening for novel natural products with antibiotic properties;
  • Obtaining high-yielding strains for antibiotic production by classical methods;
  • Improving the production of antibiotics in industrial strains through genetic manipulations;
  • Production of novel antibiotics through optimizing fermentation conditions;
  • Reprogramming strains to produce alternative antibiotics using genetic engineering;
  • Industrial-scale fed-batch fermentation;
  • Utilization and recycling of antibiotic fermentation waste.

Dr. Alexander A. Zhgun
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Fermentation is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fermentation
  • antibiotics
  • high-yielding strain
  • classical strain improvement (CSI)
  • biosynthetic gene cluster (BGC)
  • fermentation conditions
  • industrial-scale fermentation

Published Papers (7 papers)

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Research

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11 pages, 1133 KiB  
Article
The Potential of Arctic Pseudogymnoascus Fungi in the Biosynthesis of Natural Products
by Tatiana V. Antipova, Kirill V. Zaitsev, Valentina P. Zhelifonova, Sergey V. Tarlachkov, Yuri K. Grishin, Galina A. Kochkina and Mikhail B. Vainshtein
Fermentation 2023, 9(8), 702; https://doi.org/10.3390/fermentation9080702 - 26 Jul 2023
Cited by 1 | Viewed by 1245
Abstract
Scarce research into the secondary metabolites of the fungi Pseudogymnoascus spp. has shown a hidden biosynthetic potential for biologically active compounds. This work investigated the biosynthesis of secondary metabolites by two Pseudogymnoascus fungal strains, VKM F-4518 and VKM F-4519, isolated from the surface [...] Read more.
Scarce research into the secondary metabolites of the fungi Pseudogymnoascus spp. has shown a hidden biosynthetic potential for biologically active compounds. This work investigated the biosynthesis of secondary metabolites by two Pseudogymnoascus fungal strains, VKM F-4518 and VKM F-4519, isolated from the surface soil layer of the Kolyma Lowland, Russia, in the Arctic. In these strains, 16-membered trilactone macrolides, (+)-macrosphelides A and B, were identified using 1D and 2D NMR, UHRMS, and optical rotation data. In the fungi of this genus, these metabolites were found for the first time. The studied strains are highly active producers of macrosphelide A, which is being considered as a promising agent for the cure of cancer. Using the antiSMASH secondary metabolite analysis tool, we found that the genome of strain VKM F-4518 contained 32 of the biosynthetic clusters of the secondary metabolite genes (BGC) and that of VKM F-4519 had 17 BGCs. Based on the comparison of the cluster of macrotriolide genes from the fungus Paraphaeosphaeria sporulosa, we found the complete supposed cluster BGCs of macrosphelides in the genomes of two Pseudogymnoascus strains using the BLAST+ program. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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13 pages, 2695 KiB  
Article
Uncovering the Effects of the Cultivation Condition on Different Forms of Peptaibol’s Emericellipsins Production from an Alkaliphilic Fungus, Emericellopsis alkalina
by Anastasia E. Kuvarina, Maxim A. Sukonnikov, Alla V. Timofeeva, Marina V. Serebryakova, Ludmila A. Baratova, Mikhail N. Buzurnyuk, Alexander V. Golyshkin, Marina L. Georgieva and Vera S. Sadykova
Fermentation 2023, 9(5), 422; https://doi.org/10.3390/fermentation9050422 - 27 Apr 2023
Cited by 1 | Viewed by 1103
Abstract
Peptaibols (Paib) are a class of biologically active peptides isolated from fungi and molds, which have attracted the attention of medicinal chemists due to their widely ranging pharmacological properties, including their antimicrobial activity. In the present study, we investigated the effects of various [...] Read more.
Peptaibols (Paib) are a class of biologically active peptides isolated from fungi and molds, which have attracted the attention of medicinal chemists due to their widely ranging pharmacological properties, including their antimicrobial activity. In the present study, we investigated the effects of various pH levels and cultivation conditions on peptaibol complex emericellipsins A-E (EmiA-E), produced by the alkaliphilic fungus Emericellopsis alkalina. Paib production has been studied in flasks and bioreactors for different pH values ranging from 7 to 11. The study of morphological features based on light and scanning electron microscopy has revealed differences between fungi grown at different pH values and cultivation conditions. Emericellipsins have been purified, sequenced, and identified by mass spectrometry. We have found that an alkaline pH of 10 could promote emericellipsins’ biosynthesis most effectively during stationary fermentation on the 14th day of cultivation. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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14 pages, 3132 KiB  
Article
Enhanced Pentostatin Production in Actinomadura sp. by Combining ARTP Mutagenesis, Ribosome Engineering and Subsequent Fermentation Optimization
by Hongyu Zhang, Deguang Zhang, Ran Liu, Tingting Lou, Ruyue Tan and Suying Wang
Fermentation 2023, 9(4), 398; https://doi.org/10.3390/fermentation9040398 - 20 Apr 2023
Cited by 1 | Viewed by 1273
Abstract
The special structure of pentostatin causes it to possess a wide spectrum of biological and pharmacological properties, and it has been extensively employed to treat malignant tumors and is the first-line treatment for hairy cell leukemia. Pentostatin is mainly distributed in several actinomycetes [...] Read more.
The special structure of pentostatin causes it to possess a wide spectrum of biological and pharmacological properties, and it has been extensively employed to treat malignant tumors and is the first-line treatment for hairy cell leukemia. Pentostatin is mainly distributed in several actinomycetes and fungi species. However, its low titer in microbes is not able to meet medical needs. Here, we report a strain improvement strategy based on combined atmospheric and room-temperature plasma (ARTP) mutagenesis and ribosome engineering screening, as well as fermentation optimization, for enhanced pentostatin production. The original strain, Actinomadura sp. ATCC 39365, was treated with ARTP and screened by ribosome engineering to obtain one stable pentostatin high-yield mutant Actinomadura sp. S-15, which produced 86.35 mg/L pentostatin, representing a 33.79% increase compared to Actinomadura sp. ATCC 39365. qRT-PCR analysis revealed that pentostatin biosynthesis-related gene expression was significantly upregulated in Actinomadura sp. S-15. Then, to further enhance pentostatin production, the fermentation medium was optimized in flask culture and the pentostatin production of Actinomadura sp. S-15 reached 152.06 mg/L, which is the highest pentostatin production reported so far. These results demonstrate the effectiveness of combined ARTP mutation, ribosome engineering screening, and medium optimization for the enhancement of pentostatin production, and provide a methodology enabling the sustainable production of pentostatin on an industrial scale. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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14 pages, 1365 KiB  
Article
Statistical Medium Optimization for the Production of Anti-Methicillin-Resistant Staphylococcus aureus Metabolites from a Coal-Mining-Soil-Derived Streptomyces rochei CMB47
by Ibtissem Djinni, Warda Djoudi, Chahinaz Boumezoued, Halima Barchiche, Samiha Souagui, Mouloud Kecha and Ines Mancini
Fermentation 2023, 9(4), 381; https://doi.org/10.3390/fermentation9040381 - 15 Apr 2023
Cited by 2 | Viewed by 1676
Abstract
The development of novel antibacterial drugs needs urgent action due to the global emergence of antibiotic resistance. In this challenge, actinobacterial strains from arid ecosystems are proving to be promising sources of new bioactive metabolites. The identified Streptomyces rochei strain CMB47, isolated from [...] Read more.
The development of novel antibacterial drugs needs urgent action due to the global emergence of antibiotic resistance. In this challenge, actinobacterial strains from arid ecosystems are proving to be promising sources of new bioactive metabolites. The identified Streptomyces rochei strain CMB47, isolated from coal mine Saharan soil, provided an ethyl acetate extract which tested against a series of pathogens. It displayed a minimum inhibitory concentration of <0.439 µg/mL against MRSA. A statistical experimental design using a response surface methodology (RSM) based on the second-order rotatable central composite design (RCCD) was planned to develop an efficient fermentation process able to improve the bioactive metabolite production. The optimal conditions were determined for starch and NaNO3 concentrations, incubation time and the initial pH value, reaching the inhibition zone diameter of 20 mm, close to the experimental value, after validation of the model. A bioassay-guided fractionation of the crude extract provided the most active fractions, which were analyzed by HPLC equipped with a photodiode array detector and coupled online with an electrospray mass spectrometer (HPLC-DAD/ESI-MS), obtaining preliminary indications on the molecular structures of the metabolites. These results support the potential interest in further investigations into the purification and full characterization of the metabolites responsible for the biological activity observed so far. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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12 pages, 2093 KiB  
Article
Uncovering the Effects of Ammonium Sulfate on Neomycin B Biosynthesis in Streptomyces fradiae SF-2
by Xiangfei Li, Fei Yu, Kun Liu, Min Zhang, Yihan Cheng, Fang Wang, Shan Wang, Rumeng Han and Zhenglian Xue
Fermentation 2022, 8(12), 678; https://doi.org/10.3390/fermentation8120678 - 26 Nov 2022
Cited by 2 | Viewed by 1554
Abstract
The aminoglycoside antibiotic neomycin has broad antibacterial properties and is widely used in medicine and agriculture. With the discovery of neomycin’s potential applications in treating tumors and SARS-CoV-2, it is necessary to accelerate the biosynthesis of neomycin. In the present study, we investigated [...] Read more.
The aminoglycoside antibiotic neomycin has broad antibacterial properties and is widely used in medicine and agriculture. With the discovery of neomycin’s potential applications in treating tumors and SARS-CoV-2, it is necessary to accelerate the biosynthesis of neomycin. In the present study, we investigated the effects of various inorganic salts on neomycin B (the main active neomycin) biosynthesis in Streptomyces fradiae SF-2. We found that 60 mM (NH4)2SO4 could promote neomycin B biosynthesis and cell growth most effectively. Further comparative transcriptomic analyses revealed that 60 mM (NH4)2SO4 inhibited the EMP and TCA cycles and enhanced the expression of neo genes involved in the neomycin B biosynthesis pathway. Finally, a neomycin B potency of 17,399 U/mL in shaking flasks was achieved by overexpressing neoE and adding 60 mM (NH4)2SO4, corresponding to a 51.2% increase compared with the control S. fradiae SF-2. In the present study, the mechanism by which (NH4)2SO4 affects neomycin biosynthesis was revealed through transcriptomics, providing a reference for the further metabolic engineering of S. fradiae SF-2 for neomycin B production. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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Review

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38 pages, 11597 KiB  
Review
Industrial Production of Antibiotics in Fungi: Current State, Deciphering the Molecular Basis of Classical Strain Improvement and Increasing the Production of High-Yielding Strains by the Addition of Low-Molecular Weight Inducers
by Alexander A. Zhgun
Fermentation 2023, 9(12), 1027; https://doi.org/10.3390/fermentation9121027 - 16 Dec 2023
Cited by 1 | Viewed by 1967
Abstract
The natural fermentation of antibiotics, along with semi-synthetic and synthetic approaches, is one of the most important methods for their production. The majority of the antibiotic market comes from the fermentation of high-yielding (HY) fungal strains. These strains have been obtained since the [...] Read more.
The natural fermentation of antibiotics, along with semi-synthetic and synthetic approaches, is one of the most important methods for their production. The majority of the antibiotic market comes from the fermentation of high-yielding (HY) fungal strains. These strains have been obtained since the 1950s from wild-type (WT) isolates as a result of classical strain improvement (CSI) programs primarily involving multi-round random mutagenesis and screening. However, the molecular basis leading to high-yield production was unknown. In recent years, due to the application of multiomic approaches, key changes that occur in CSI programs, with WT strains that become HY industrial producers of a particular antibiotic, have begun to be understood. It becomes obvious that, during CSI, certain universal events are selected, which lead both to a direct increase in the production of the target metabolite and affect other vital processes of the cell (side mutations). These key events include: the upregulation of the target biosynthetic gene cluster (BGC), changes in the system of global regulation, disruption of alternative BGCs, the rearrangement of energy fluxes in favor of the target SM (secondary metabolite), changes in the regulation of the response to stress, and the redirection of primary metabolic pathways to obtain more precursors for target production. This knowledge opens up the possibility of both introducing targeted changes using genetic engineering methods when creating new producers and increasing the production of CSI strains as a result of fermentation with low-molecular compounds, targeted to compensate for the effects of side mutations. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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15 pages, 1849 KiB  
Review
Pentostatin Biosynthesis Pathway Elucidation and Its Application
by Hongyu Zhang, Ran Liu, Tingting Lou, Pei Zhao and Suying Wang
Fermentation 2022, 8(9), 459; https://doi.org/10.3390/fermentation8090459 - 14 Sep 2022
Cited by 2 | Viewed by 2290
Abstract
Pentostatin (PNT), a nucleoside antibiotic with a 1,3-diazo ring structure, is distributed in several actinomycetes and fungi species. Its special structure makes PNT possess a wide spectrum of biological and pharmacological properties, such as antibacterial, antitrypanosomal, anticancer, antiviral, herbicidal, insecticidal, and immunomodulatory effects. [...] Read more.
Pentostatin (PNT), a nucleoside antibiotic with a 1,3-diazo ring structure, is distributed in several actinomycetes and fungi species. Its special structure makes PNT possess a wide spectrum of biological and pharmacological properties, such as antibacterial, antitrypanosomal, anticancer, antiviral, herbicidal, insecticidal, and immunomodulatory effects. Because of the promising adenosine deaminase inhibitory activity of PNT, its extensive application in the clinical treatment of malignant tumors has been extensively studied. However, the fermentation level of microbial-derived PNT is low and cannot meet medical needs. Because the biosynthesis pathway of PNT is obscure, only high-yield mutant screening and optimization of medium components and fermentation processes have been conducted for enhancing its production. Recently, the biosynthesis pathways of PNT in actinomycetes and fungi hosts have been revealed successively, and the large-scale production of PNT by systematic metabolic engineering will become an inevitable trend. Therefore, this review covers all aspects of PNT research, in which major advances in understanding the resource microorganisms, mechanism of action, and biosynthesis pathway of PNT were achieved and diverse clinical applications of PNT were emphasized, and it will lay the foundation for commercial transformation and industrial technology of PNT based on systematic metabolic engineering. Full article
(This article belongs to the Special Issue Pharmaceutical Fermentation: Antibiotic Production and Processing)
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