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Microorganisms
Special Issues
Microbial Non-Ribosomal Synthesis of Secondary Metabolites
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Microbial Non-Ribosomal Synthesis of Secondary Metabolites

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Microbial Biotechnology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 23322

Special Issue Editors

Dr. Stéphane Cociancich

E-Mail Website
Guest Editor
Cirad (Centre de coopération internationale en recherche agronomique pour le développement), UMR PHIM (Plant Health Institute of Montpellier), TA A-120/K, Campus International de Baillarguet, F-34398 Montpellier CEDEX 5, France
Interests: non-ribosomal peptide synthesis; polyketide synthesis; secondary metabolites; natural products; plant-microbe interactions; plant pathology; biocontrol; quorum sensing; genome mining; silent biosynthetic genes clusters awakening; isolation of metabolites by HPLC; Streptomyces; Burkholderia; Xanthomonas; Dickeya
Prof. Valérie Leclère

E-Mail Website
Guest Editor
Joint Research Unit INRAE Ulille ULiège UPJV, BioEcoAgro 1158, Charles Viollette Institute, Lille, France
Interests: non-ribosomal peptides; secondary metabolites; natural products; lipopeptides; siderophores; plant-microbe interactions; biocontrol; genome mining; bioinformatics; Bacillus; Pseudomonas; Burkholderia; Streptomyces; Norine database

Special Issue Information

Dear Colleagues,

Microbial secondary metabolites are natural products displaying various therapeutically or agrochemically relevant biological activities (e.g., antibiotics, antifungal or anti-proliferative agents, siderophores, toxins). Interestingly, bacteria and fungi produce many of these compounds courtesy of non-ribosomal biosynthetic enzymatic pathways involving multimodular mega-enzymes called non-ribosomal peptide synthetases and polyketide synthases. These mega-enzymes exhibit a fascinating thiotemplate-based characteristic architecture that permits the iterative assembly of proteinogenic or non-proteinogenic building blocks (e.g., aminoacids, hydroxyacids, acyl-thioesters, fatty acids, chromophores) into growing polypeptidic or polyketid chains as in an assembly line. To date, more than 500 different building blocks have been identified in non-ribosomally synthesized secondary metabolites, hence resulting in a near-infinity of complex structures.

Genes encoding these huge synthetases are generally clustered with other genes encoding regulation, immunity, transport or tailoring (among others) proteins, leading to the concept of biosynthetic genes clusters being responsible for the biosynthesis, structural modifications, regulation and transport of the corresponding secondary metabolites. For decades, new secondary metabolites have been discovered through screenings of biological activities, but increasing re-discoveries of already-known secondary metabolites have proven that this strategy has become inefficient lately. However, the current exponential increase of available genomic sequences (including sequences from thousands complete microbial genomes) suddenly gives access to a huge amount of information which unravels the potential of microorganisms to produce secondary metabolites exhibiting new structural scaffolds, and therefore new biological activities, which is largely underestimated. Indeed, in silico analyses of these genomes (also known as genome mining) show that most of the biosynthetic genes clusters remain silent under usual laboratory conditions. The actual challenge remains to exploit this potential, as many “awakening” techniques for these silent biosynthetic gene clusters are yet available.

With this Special Issue, we aim at presenting current and future directions in understanding the non-ribosomal biosynthesis of microbial secondary metabolites. This includes but is not limited to the identification of new biosynthetic pathways in microbial genomes, the deciphering of these pathways, the structural elucidation of the synthesized compounds, the functional characterization of the biosynthetic mega-enzymes and their products, or the use of synthetic biology to generate structural analogues of the natural products.

As the Guest Editors of this Special Issue, we kindly invite you to submit research articles, review articles, and short communications related to the field of non-ribosomal synthesis of secondary metabolites.

Dr. Stéphane Cociancich
Prof. Valérie Leclère
Guest Editors

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. Microorganisms 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 2700 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

  • secondary metabolites
  • non-ribosomal peptide synthesis
  • polyketide synthesis
  • biosynthetic pathway
  • genome mining
  • metabolic engineering
  • synthetic biology
  • structural analogues
  • biological activities
  • biocontrol

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Published Papers (7 papers)

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Editorial

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4 pages, 201 KiB  
Editorial
Editorial for the Special Issue “Microbial Nonribosomal Synthesis of Secondary Metabolites”
by Stéphane Cociancich and Valérie Leclère
Microorganisms 2022, 10(5), 1064; https://doi.org/10.3390/microorganisms10051064 - 21 May 2022
Viewed by 1656
Abstract
Microbial secondary metabolites are natural products that display various therapeutical or agrochemical relevant activities (e [...] Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)

Research

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12 pages, 548 KiB  
Article
Taxonomic Positions of a Nyuzenamide-Producer and Its Closely Related Strains
by Hisayuki Komaki, Yasuhiro Igarashi and Tomohiko Tamura
Microorganisms 2022, 10(2), 349; https://doi.org/10.3390/microorganisms10020349 - 2 Feb 2022
Cited by 9 | Viewed by 1922
Abstract
Streptomyces sp. N11-34 is a producer of bicyclic peptides named nyuzenamides A and B. We elucidated its taxonomic position and surveyed its nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) gene clusters by whole genome analysis. Streptomyces sp. N11-34 showed 16S rRNA gene [...] Read more.
Streptomyces sp. N11-34 is a producer of bicyclic peptides named nyuzenamides A and B. We elucidated its taxonomic position and surveyed its nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) gene clusters by whole genome analysis. Streptomyces sp. N11-34 showed 16S rRNA gene sequence similarities of 99.9% and 99.8% to Streptomyces hygroscopicus NBRC 13472T and Streptomyces demainii NRRL B-1478T, respectively. Although these members formed a clade in a phylogenetic tree based on 16S rRNA gene sequences, the clade split into two closely related subclades in multilocus sequence analysis (MLSA). One included Streptomyces sp. N11-34, S. demainii NRRL B-1478T, S. hygroscopicus NBRC 100766, S. hygroscopicus NBRC 16556 and S. hygroscopicus TP-A0867 and the other comprised S. hygroscopicus NBRC 13472T and S. hygroscopicus NBRC 12859. These phylogenetic relationships were supported by phylogenomic analysis. Although Streptomyces sp. N11-34 was classified to S. hygroscopicus at the species level based on MLSA evolutionary distances and DNA–DNA relatedness, these distances and relatedness of members between the two subclades were comparatively far (0.004–0.006) and low (75.4–76.4%), respectively. Streptomyces sp. N11-34 possessed six NRPS, seven PKS and four hybrid PKS/NRPS gene clusters in the genome. Among the seventeen, ten were identified to be biosynthetic gene clusters (BGCs) of nyuzenamide, echoside, coelichelin, geldanamycin, mediomycin, nigericin, azalomycin, spore pigment, alchivemycin and totopotensamide, whereas the remaining seven were orphan in our bioinformatic analysis. All seventeen are conserved in S. hygroscopicus NBRC 100766, S. hygroscopicus NBRC 16556 and S. hygroscopicus TP-A0867. In contrast, S. hygroscopicus NBRC 13472T and S. hygroscopicus NBRC 12859 lacked the BGCs of alchivemycin, totopotensamide, a nonribosomal peptide and a hybrid polyketide/nonribosomal peptide compound. This difference was in a good accordance with the abovementioned phylogenetic relationship. Based on phenotypic differences in addition to phylogenetic relationship, DNA–DNA relatedness and BGCs, strains of S. hygroscopicus should be reclassified to two subspecies: S. hygroscopicus subsp. hygroscopicus and a new subspecies, for which we proposed S. hygroscopicus subsp. sporocinereus subsp. nov. The type strain is NBRC 100766T (=ATCC 43692T = DSM 41460T = INMI 32T = JCM 9093T = NRRL B-16376T = VKM Ac-312T). S. demainii was classified in this subspecies. Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)
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11 pages, 1164 KiB  
Article
Bonsecamin: A New Cyclic Pentapeptide Discovered through Heterologous Expression of a Cryptic Gene Cluster
by Constanze Lasch, Marc Stierhof, Marta Rodríguez Estévez, Maksym Myronovskyi, Josef Zapp and Andriy Luzhetskyy
Microorganisms 2021, 9(8), 1640; https://doi.org/10.3390/microorganisms9081640 - 31 Jul 2021
Cited by 5 | Viewed by 2776
Abstract
The intriguing structural complexity of molecules produced by natural organisms is uncontested. Natural scaffolds serve as an important basis for the development of molecules with broad applications, e.g., therapeutics or agrochemicals. Research in recent decades has demonstrated that by means of classic metabolite [...] Read more.
The intriguing structural complexity of molecules produced by natural organisms is uncontested. Natural scaffolds serve as an important basis for the development of molecules with broad applications, e.g., therapeutics or agrochemicals. Research in recent decades has demonstrated that by means of classic metabolite extraction from microbes only a small portion of natural products can be accessed. The use of genome mining and heterologous expression approaches represents a promising way to discover new natural compounds. In this paper we report the discovery of a novel cyclic pentapeptide called bonsecamin through the heterologous expression of a cryptic NRPS gene cluster from Streptomyces albus ssp. chlorinus NRRL B-24108 in Streptomyces albus Del14. The new compound was successfully isolated and structurally characterized using NMR. The minimal set of genes required for bonsecamin production was determined through bioinformatic analysis and gene deletion experiments. A biosynthetic route leading to the production of bonsecamin is proposed in this paper. Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)
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14 pages, 1077 KiB  
Article
Cyclofaulknamycin with the Rare Amino Acid D-capreomycidine Isolated from a Well-Characterized Streptomyces albus Strain
by Liliya Horbal, Marc Stierhof, Anja Palusczak, Nikolas Eckert, Josef Zapp and Andriy Luzhetskyy
Microorganisms 2021, 9(8), 1609; https://doi.org/10.3390/microorganisms9081609 - 28 Jul 2021
Cited by 5 | Viewed by 3062
Abstract
Targeted genome mining is an efficient method of biosynthetic gene cluster prioritization within constantly growing genome databases. Using two capreomycidine biosynthesis genes, alpha-ketoglutarate-dependent arginine beta-hydroxylase and pyridoxal-phosphate-dependent aminotransferase, we identified two types of clusters: one type containing both genes involved in the biosynthesis [...] Read more.
Targeted genome mining is an efficient method of biosynthetic gene cluster prioritization within constantly growing genome databases. Using two capreomycidine biosynthesis genes, alpha-ketoglutarate-dependent arginine beta-hydroxylase and pyridoxal-phosphate-dependent aminotransferase, we identified two types of clusters: one type containing both genes involved in the biosynthesis of the abovementioned moiety, and other clusters including only arginine hydroxylase. Detailed analysis of one of the clusters, the flk cluster from Streptomyces albus, led to the identification of a cyclic peptide that contains a rare D-capreomycidine moiety for the first time. The absence of the pyridoxal-phosphate-dependent aminotransferase gene in the flk cluster is compensated by the XNR_1347 gene in the S. albus genome, whose product is responsible for biosynthesis of the abovementioned nonproteinogenic amino acid. Herein, we report the structure of cyclofaulknamycin and the characteristics of its biosynthetic gene cluster, biosynthesis and bioactivity profile. Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)
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11 pages, 1850 KiB  
Article
Discovery and Heterologous Production of New Cyclic Depsibosamycins
by Marc Stierhof, Maksym Myronovskyi, Josef Zapp and Andriy Luzhetskyy
Microorganisms 2021, 9(7), 1396; https://doi.org/10.3390/microorganisms9071396 - 28 Jun 2021
Cited by 2 | Viewed by 2717
Abstract
Streptomyces are producers of valuable secondary metabolites with unique scaffolds that perform a plethora of biological functions. Nonribosomal peptides are of special interest due to their variety and complexity. They are synthesized by nonribosomal peptide synthetases, large biosynthetic machineries that are encoded in [...] Read more.
Streptomyces are producers of valuable secondary metabolites with unique scaffolds that perform a plethora of biological functions. Nonribosomal peptides are of special interest due to their variety and complexity. They are synthesized by nonribosomal peptide synthetases, large biosynthetic machineries that are encoded in the genome of many Streptomyces species. The identification of new peptides and the corresponding biosynthetic gene clusters is of major interest since knowledge can be used to facilitate combinatorial biosynthesis and chemical semisynthesis of natural products. The recently discovered bosamycins are linear octapeptides with an interesting 5-OMe tyrosine moiety and various modifications at the N-terminus. In this study, the new cyclic depsibosamycins B, C, and D from Streptomyces aurantiacus LU19075 were discovered. In comparison to the linear bosamycins B, C, and D, which were also produced by the strain, the cyclic depsibosamycins showed a side-chain-to-tail lactonization of serine and glycine, leading to a ring of four amino acids. In silico identification and heterologous expression of the depsibosamycin (dbm) gene cluster indicated that the cyclic peptides, rather than the linear derivatives, are the main products of the cluster. Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)
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13 pages, 2301 KiB  
Article
One Pathway, Two Cyclic Non-Ribosomal Pentapeptides: Heterologous Expression of BE-18257 Antibiotics and Pentaminomycins from Streptomyces cacaoi CA-170360
by Fernando Román-Hurtado, Marina Sánchez-Hidalgo, Jesús Martín, Francisco Javier Ortiz-López, Daniel Carretero-Molina, Fernando Reyes and Olga Genilloud
Microorganisms 2021, 9(1), 135; https://doi.org/10.3390/microorganisms9010135 - 8 Jan 2021
Cited by 8 | Viewed by 3131
Abstract
The strain Streptomyces cacaoi CA-170360 produces the cyclic pentapeptides pentaminomycins A–H and BE-18257 A–C, two families of cyclopeptides synthesized by two non-ribosomal peptide synthetases encoded in tandem within the same biosynthetic gene cluster. In this work, we have cloned and confirmed the heterologous [...] Read more.
The strain Streptomyces cacaoi CA-170360 produces the cyclic pentapeptides pentaminomycins A–H and BE-18257 A–C, two families of cyclopeptides synthesized by two non-ribosomal peptide synthetases encoded in tandem within the same biosynthetic gene cluster. In this work, we have cloned and confirmed the heterologous expression of this biosynthetic gene cluster, demonstrating that each of the non-ribosomal peptide synthetases present in the cluster is involved in the biosynthesis of each group of cyclopeptides. In addition, we discuss the involvement of a stand-alone enzyme belonging to the Penicillin Binding Protein family in the release and macrocyclization of the peptides. Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)
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Review

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19 pages, 2208 KiB  
Review
Nonribosomal Peptide Synthesis Definitely Working Out of the Rules
by Matthieu Duban, Stéphane Cociancich and Valérie Leclère
Microorganisms 2022, 10(3), 577; https://doi.org/10.3390/microorganisms10030577 - 7 Mar 2022
Cited by 22 | Viewed by 6540
Abstract
Nonribosomal peptides are microbial secondary metabolites exhibiting a tremendous structural diversity and a broad range of biological activities useful in the medical and agro-ecological fields. They are built up by huge multimodular enzymes called nonribosomal peptide synthetases. These synthetases are organized in modules [...] Read more.
Nonribosomal peptides are microbial secondary metabolites exhibiting a tremendous structural diversity and a broad range of biological activities useful in the medical and agro-ecological fields. They are built up by huge multimodular enzymes called nonribosomal peptide synthetases. These synthetases are organized in modules constituted of adenylation, thiolation, and condensation core domains. As such, each module governs, according to the collinearity rule, the incorporation of a monomer within the growing peptide. The release of the peptide from the assembly chain is finally performed by a terminal core thioesterase domain. Secondary domains with modifying catalytic activities such as epimerization or methylation are sometimes included in the assembly lines as supplementary domains. This assembly line structure is analyzed by bioinformatics tools to predict the sequence and structure of the final peptides according to the sequence of the corresponding synthetases. However, a constantly expanding literature unravels new examples of nonribosomal synthetases exhibiting very rare domains and noncanonical organizations of domains and modules, leading to several amazing strategies developed by microorganisms to synthesize nonribosomal peptides. In this review, through several examples, we aim at highlighting these noncanonical pathways in order for the readers to perceive their complexity. Full article
(This article belongs to the Special Issue Microbial Non-Ribosomal Synthesis of Secondary Metabolites)
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