scholarly journals Qinichelins, novel catecholate-hydroxamate siderophores synthesized via a multiplexed convergent biosynthesis pathway

2017 ◽  
Author(s):  
Jacob Gubbens ◽  
Changsheng Wu ◽  
Hua Zhu ◽  
Dmitri V. Filippov ◽  
Bogdan I. Florea ◽  
...  
Keyword(s):  
Natural Product ◽  
Expression Profiles ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Chemical Diversity ◽  
Orphan Gene ◽  
Natural Product Discovery ◽  
Bioinformatic Tools ◽  
Hydroxamate Siderophores ◽  
Protein Expression Profiles

ABSTRACTThe explosive increase in genome sequencing and the advances in bioinformatic tools have revolutionized the rationale for natural product discovery from actinomycetes. In particular, this has revealed that actinomycete genomes contain numerous orphan gene clusters that have the potential to specify many yet unknown bioactive specialized metabolites, representing a huge unexploited pool of chemical diversity. Here, we describe the discovery of a novel group of catecholate-hydroxamate siderophores termed qinichelins (2–5) fromStreptomycessp. MBT76. Correlation between the metabolite levels and the protein expression profiles identified the biosynthetic gene cluster (BGC; namedqch) most likely responsible for qinichelin biosynthesis. The structure of the molecules was elucidated by bioinformatics, mass spectrometry and NMR. Synthesis of the qinichelins requires the interplay between four gene clusters, for its synthesis and for precursor supply. This biosynthetic complexity provides new insights into the challenges scientists face when applying synthetic biology approaches for natural product discovery.Pride repository reviewer account details:URL:https://www.ebi.ac.uk/pride/archive/loginProject accession: PXD006577Username: [email protected]: 3H0iM1FK

scholarly journals New Kendomycin Derivative Isolated from Streptomyces sp. Cl 58-27

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6834
Author(s):  
Constanze Paulus ◽  
Oleksandr Gromyko ◽  
Andriy Luzhetskyy
Keyword(s):  
Nmr Spectroscopy ◽  
Natural Product ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene ◽  
Streptomyces Sp ◽  
Bioinformatic Tools ◽  
Isolation And Characterization ◽  
Metabolism Gene

In the course of screening new streptomycete strains, the strain Streptomyces sp. Cl 58-27 caught our attention due to its interesting secondary metabolite production profile. Here, we report the isolation and characterization of an ansamycin natural product that belongs structurally to the already known kendomycins. The structure of the new kendomycin E was elucidated using NMR spectroscopy, and the corresponding biosynthetic gene cluster was identified by sequencing the genome of Streptomyces sp. Cl 58-27 and conducting a detailed analysis of secondary metabolism gene clusters using bioinformatic tools.

scholarly journals The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking

mSystems ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Daniela B. B. Trivella ◽  
Rafael de Felicio
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Natural Product ◽  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Chemical Compounds ◽  
Gene Clusters ◽  
Tandem Mass ◽  
Molecular Networking ◽  
Natural Product Discovery

ABSTRACT Natural products are the richest source of chemical compounds for drug discovery. Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic) gene clusters under laboratory cultivation. Further progress in compound detection, such as the development of the tandem mass spectrometry (MS/MS) molecular networking approach, has contributed to the discovery of novel bacterial natural products. The latter can be applied directly to bacterial crude extracts for identifying and dereplicating known compounds, therefore assisting the prioritization of extracts containing novel natural products, for example. In our opinion, these three approaches—genome mining, silent pathway induction, and MS-based molecular networking—compose the tripod for modern bacterial natural product discovery and will be discussed in this perspective.

scholarly journals Genomic Assemblies of Members of Burkholderia and Related Genera as a Resource for Natural Product Discovery

2020 ◽  
Vol 9 (42) ◽  
Author(s):  
Alex J. Mullins ◽  
Cerith Jones ◽  
Matthew J. Bull ◽  
Gordon Webster ◽  
Julian Parkhill ◽  
...  
Keyword(s):  
Natural Product ◽  
Genome Mining ◽  
Genomic Analysis ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Natural Product Discovery

ABSTRACT The genomes of 450 members of Burkholderiaceae, isolated from clinical and environmental sources, were sequenced and assembled as a resource for genome mining. Genomic analysis of the collection has enabled the identification of multiple metabolites and their biosynthetic gene clusters, including the antibiotics gladiolin, icosalide A, enacyloxin, and cepacin A.

scholarly journals BiG-SLiCE: A Highly Scalable Tool Maps the Diversity of 1.2 Million Biosynthetic Gene Clusters

2020 ◽  
Author(s):  
Satria A. Kautsar ◽  
Justin J. J. van der Hooft ◽  
Dick de Ridder ◽  
Marnix H. Medema
Keyword(s):  
Natural Product ◽  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Genomic Diversity ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Microbial Genomes ◽  
Natural Product Discovery ◽  
User Friendly

AbstractBackgroundGenome mining for Biosynthetic Gene Clusters (BGCs) has become an integral part of natural product discovery. The >200,000 microbial genomes now publicly available hold information on abundant novel chemistry. One way to navigate this vast genomic diversity is through comparative analysis of homologous BGCs, which allows identification of cross-species patterns that can be matched to the presence of metabolites or biological activities. However, current tools suffer from a bottleneck caused by the expensive network-based approach used to group these BGCs into Gene Cluster Families (GCFs).ResultsHere, we introduce BiG-SLiCE, a tool designed to cluster massive numbers of BGCs. By representing them in Euclidean space, BiG-SLiCE can group BGCs into GCFs in a non-pairwise, near-linear fashion. We used BiG-SLiCE to analyze 1,225,071 BGCs collected from 209,206 publicly available microbial genomes and metagenome-assembled genomes (MAGs) within ten days on a typical 36-cores CPU server. We demonstrate the utility of such analyses by reconstructing a global map of secondary metabolic diversity across taxonomy to identify uncharted biosynthetic potential. BiG-SLiCE also provides a "query mode" that can efficiently place newly sequenced BGCs into previously computed GCFs, plus a powerful output visualization engine that facilitates user-friendly data exploration.ConclusionsBiG-SLiCE opens up new possibilities to accelerate natural product discovery and offers a first step towards constructing a global, searchable interconnected network of BGCs. As more genomes get sequenced from understudied taxa, more information can be mined to highlight their potentially novel chemistry. BiG-SLiCE is available via https://github.com/medema-group/bigslice.

scholarly journals Expanded Natural Product Diversity Revealed by Analysis of Lanthipeptide-Like Gene Clusters in Actinobacteria

2015 ◽  
Vol 81 (13) ◽  
pp. 4339-4350 ◽  
Author(s):  
Qi Zhang ◽  
James R. Doroghazi ◽  
Xiling Zhao ◽  
Mark C. Walker ◽  
Wilfred A. van der Donk
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Cluster ◽  
Posttranslational Modifications ◽  
Large Scale ◽  
Biological Activities ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Content Type ◽  
Modified Peptides

ABSTRACTLanthionine-containing peptides (lanthipeptides) are a rapidly growing family of polycyclic peptide natural products belonging to the large class of ribosomally synthesized and posttranslationally modified peptides (RiPPs). Lanthipeptides are widely distributed in taxonomically distant species, and their currently known biosynthetic systems and biological activities are diverse. Building on the recent natural product gene cluster family (GCF) project, we report here large-scale analysis of lanthipeptide-like biosynthetic gene clusters fromActinobacteria. Our analysis suggests that lanthipeptide biosynthetic pathways, and by extrapolation the natural products themselves, are much more diverse than currently appreciated and contain many different posttranslational modifications. Furthermore, lanthionine synthetases are much more diverse in sequence and domain topology than currently characterized systems, and they are used by the biosynthetic machineries for natural products other than lanthipeptides. The gene cluster families described here significantly expand the chemical diversity and biosynthetic repertoire of lanthionine-related natural products. Biosynthesis of these novel natural products likely involves unusual and unprecedented biochemistries, as illustrated by several examples discussed in this study. In addition, class IV lanthipeptide gene clusters are shown not to be silent, setting the stage to investigate their biological activities.

scholarly journals Comparative transcriptomics as a guide to natural product discovery and biosynthetic gene cluster functionality

2017 ◽  
Vol 114 (52) ◽  
pp. E11121-E11130 ◽  
Author(s):  
Gregory C. A. Amos ◽  
Takayoshi Awakawa ◽  
Robert N. Tuttle ◽  
Anne-Catrin Letzel ◽  
Min Cheol Kim ◽  
...  
Keyword(s):  
Natural Product ◽  
Gene Cluster ◽  
Genetic Manipulation ◽  
Expression Profiles ◽  
Genome Mining ◽  
Gene Clusters ◽  
Comparative Transcriptomics ◽  
Regulatory Control ◽  
Biosynthetic Gene ◽  
Metabolomics Data

Bacterial natural products remain an important source of new medicines. DNA sequencing has revealed that a majority of natural product biosynthetic gene clusters (BGCs) maintained in bacterial genomes have yet to be linked to the small molecules whose biosynthesis they encode. Efforts to discover the products of these orphan BGCs are driving the development of genome mining techniques based on the premise that many are transcriptionally silent during normal laboratory cultivation. Here, we employ comparative transcriptomics to assess BGC expression among four closely related strains of marine bacteria belonging to the genusSalinispora. The results reveal that slightly more than half of the BGCs are expressed at levels that should facilitate product detection. By comparing the expression profiles of similar gene clusters in different strains, we identified regulatory genes whose inactivation appears linked to cluster silencing. The significance of these subtle differences between expressed and silent BGCs could not have been predicted a priori and was only revealed by comparative transcriptomics. Evidence for the conservation of silent clusters among a larger number of strains for which genome sequences are available suggests they may be under different regulatory control from the expressed forms or that silencing may represent an underappreciated mechanism of gene cluster evolution. Coupling gene expression and metabolomics data established a bioinformatic link between the salinipostins and their associated BGC, while genetic manipulation established the genetic basis for this series of compounds, which were previously unknown fromSalinispora pacifica.

Native and engineered promoters in natural product discovery

2016 ◽  
Vol 33 (8) ◽  
pp. 1006-1019 ◽  
Author(s):  
Maksym Myronovskyi ◽  
Andriy Luzhetskyy
Keyword(s):  
Natural Product ◽  
Transcriptional Activation ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Natural Product Discovery

Transcriptional activation of biosynthetic gene clusters.

scholarly journals Natural Product Gene Clusters in the Filamentous Nostocales Cyanobacterium HT-58-2

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 356
Author(s):  
Xiaohe Jin ◽  
Eric S. Miller ◽  
Jonathan S. Lindsey
Keyword(s):  
Natural Products ◽  
Nitrogen Fixation ◽  
Natural Product ◽  
Microbial Consortium ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Nitrogen Stress ◽  
Biosynthetic Gene ◽  
Tetrapyrrole Biosynthesis ◽  
The Rich

Cyanobacteria are known as rich repositories of natural products. One cyanobacterial-microbial consortium (isolate HT-58-2) is known to produce two fundamentally new classes of natural products: the tetrapyrrole pigments tolyporphins A–R, and the diterpenoid compounds tolypodiol, 6-deoxytolypodiol, and 11-hydroxytolypodiol. The genome (7.85 Mbp) of the Nostocales cyanobacterium HT-58-2 was annotated previously for tetrapyrrole biosynthesis genes, which led to the identification of a putative biosynthetic gene cluster (BGC) for tolyporphins. Here, bioinformatics tools have been employed to annotate the genome more broadly in an effort to identify pathways for the biosynthesis of tolypodiols as well as other natural products. A putative BGC (15 genes) for tolypodiols has been identified. Four BGCs have been identified for the biosynthesis of other natural products. Two BGCs related to nitrogen fixation may be relevant, given the association of nitrogen stress with production of tolyporphins. The results point to the rich biosynthetic capacity of the HT-58-2 cyanobacterium beyond the production of tolyporphins and tolypodiols.

scholarly journals Comparative Genomics among Closely Related Streptomyces Strains Revealed Specialized Metabolite Biosynthetic Gene Cluster Diversity

Antibiotics ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 86 ◽  
Author(s):  
Cláudia Vicente ◽  
Annabelle Thibessard ◽  
Jean-Noël Lorenzi ◽  
Mabrouka Benhadj ◽  
Laurence Hôtel ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sequence Data ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Core Gene ◽  
Chemical Diversity ◽  
Specific Gene ◽  
Biosynthetic Gene ◽  
Single Strain ◽  
Specialized Metabolites

Specialized metabolites are of great interest due to their possible industrial and clinical applications. The increasing number of antimicrobial resistant infectious agents is a major health threat and therefore, the discovery of chemical diversity and new antimicrobials is crucial. Extensive genomic data from Streptomyces spp. confirm their production potential and great importance. Genome sequencing of the same species strains indicates that specialized metabolite biosynthetic gene cluster (SMBGC) diversity is not exhausted, and instead, a pool of novel specialized metabolites still exists. Here, we analyze the genome sequence data from six phylogenetically close Streptomyces strains. The results reveal that the closer strains are phylogenetically, the number of shared gene clusters is higher. Eight specialized metabolites comprise the core metabolome, although some strains have only six core gene clusters. The number of conserved gene clusters common between the isolated strains and their closest phylogenetic counterparts varies from nine to 23 SMBGCs. However, the analysis of these phylogenetic relationships is not affected by the acquisition of gene clusters, probably by horizontal gene transfer events, as each strain also harbors strain-specific SMBGCs. Between one and 15 strain-specific gene clusters were identified, of which up to six gene clusters in a single strain are unknown and have no identifiable orthologs in other species, attesting to the existing SMBGC novelty at the strain level.

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