scholarly journals Deliberations on Natural Products and Future Directions in the Pharmaceutical Industry

2021 ◽  
Vol 75 (7) ◽  
pp. 620-633
Author(s):  
Kathrin Buntin ◽  
Peter Ertl ◽  
Dominic Hoepfner ◽  
Philipp Krastel ◽  
Edward J. Oakeley ◽  
...  
Keyword(s):  
Natural Products ◽  
Chemical Space ◽  
Pharmaceutical Research ◽  
Gene Clusters ◽  
Drug Market ◽  
Special Equipment ◽  
Research Areas ◽  
Biological Target ◽  
Synthetic Derivative ◽  
Fungal Genes

Natural Products (NPs) are molecular' special equipment ' that impart survival benefits on their producers in nature. Due to their evolved functions to modulate biology these privileged metabolites are substantially represented in the drug market and are continuing to contribute to the discovery of innovative medicines such as the recently approved semi-synthetic derivative of the bacterial alkaloid staurosporin in oncology indications. The innovation of low molecular weight compounds in modern drug discovery is built on rapid progress in chemical, molecular biological, pharmacological and data sciences, which together provide a rich understanding of disease-driving molecular interactions and how to modulate them. NPs investigated in these pharmaceutical research areas create new perspectives on their chemical and biological features and thereby new chances to advance medical research. New methods in analytical chemistry linked with searchable NP-databases solved the issue of reisolation and enabled targeted and efficient access to novel molecules from nature. Cheminformatics delivers high resolution descriptions of NPs and explores the substructures that systematically map NP-chemical space by sp3-enriched fragments. Whole genome sequencing has revealed the existence of collocated gene clusters that form larger functional entities together with proximate resistance factors thus avoiding self-inhibition of the encoded metabolites. The analysis of bacterial and fungal genes provides tantalizing glimpses of new compound-target pairs of therapeutic value. Furthermore, a dedicated investigation of structurally unique, selectively active NPs in chemical biology demonstrates their extraordinary power as shuttles between new biological target spaces of pharmaceutical relevance.

scholarly journals Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining

2016 ◽  
Vol 113 (42) ◽  
pp. E6343-E6351 ◽  
Author(s):  
Michael A. Skinnider ◽  
Chad W. Johnston ◽  
Robyn E. Edgar ◽  
Chris A. Dejong ◽  
Nishanth J. Merwin ◽  
...  
Keyword(s):  
Natural Products ◽  
Genome Sequencing ◽  
Sequence Data ◽  
Chemical Space ◽  
Biological Activities ◽  
Global Analysis ◽  
Gene Clusters ◽  
Systematic Investigation ◽  
Chemical Structures ◽  
Modified Peptides

Microbial natural products are an evolved resource of bioactive small molecules, which form the foundation of many modern therapeutic regimes. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) represent a class of natural products which have attracted extensive interest for their diverse chemical structures and potent biological activities. Genome sequencing has revealed that the vast majority of genetically encoded natural products remain unknown. Many bioinformatic resources have therefore been developed to predict the chemical structures of natural products, particularly nonribosomal peptides and polyketides, from sequence data. However, the diversity and complexity of RiPPs have challenged systematic investigation of RiPP diversity, and consequently the vast majority of genetically encoded RiPPs remain chemical “dark matter.” Here, we introduce an algorithm to catalog RiPP biosynthetic gene clusters and chart genetically encoded RiPP chemical space. A global analysis of 65,421 prokaryotic genomes revealed 30,261 RiPP clusters, encoding 2,231 unique products. We further leverage the structure predictions generated by our algorithm to facilitate the genome-guided discovery of a molecule from a rare family of RiPPs. Our results provide the systematic investigation of RiPP genetic and chemical space, revealing the widespread distribution of RiPP biosynthesis throughout the prokaryotic tree of life, and provide a platform for the targeted discovery of RiPPs based on genome sequencing.

scholarly journals Recapitulation of the evolution of biosynthetic gene clusters reveals hidden chemical diversity on bacterial genomes

2015 ◽  
Author(s):  
Pablo Cruz-Morales ◽  
Christian E. Martínez-Guerrero ◽  
Marco A. Morales-Escalante ◽  
Luis Yáñez-Guerra ◽  
Johannes Florian Kopp ◽  
...  
Keyword(s):  
Natural Products ◽  
Chemical Space ◽  
Streptomyces Coelicolor ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Chemical Diversity ◽  
Biosynthetic Gene ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters

AbstractNatural products have provided humans with antibiotics for millennia. However, a decline in the pace of chemical discovery exerts pressure on human health as antibiotic resistance spreads. The empirical nature of current genome mining approaches used for natural products research limits the chemical space that is explored. By integration of evolutionary concepts related to emergence of metabolism, we have gained fundamental insights that are translated into an alternative genome mining approach, termed EvoMining. As the founding assumption of EvoMining is the evolution of enzymes, we solved two milestone problems revealing unprecedented conversions. First, we report the biosynthetic gene cluster of the ‘orphan’ metabolite leupeptin in Streptomyces roseus. Second, we discover an enzyme involved in formation of an arsenic-carbon bond in Streptomyces coelicolor and Streptomyces lividans. This work provides evidence that bacterial chemical repertoire is underexploited, as well as an approach to accelerate the discovery of novel antibiotics from bacterial genomes.

scholarly journals An interpreted atlas of biosynthetic gene clusters from 1,000 fungal genomes

2021 ◽  
Vol 118 (19) ◽  
pp. e2020230118
Author(s):  
Matthew T. Robey ◽  
Lindsay K. Caesar ◽  
Milton T. Drott ◽  
Nancy P. Keller ◽  
Neil L. Kelleher
Keyword(s):  
Natural Products ◽  
Chemical Space ◽  
Genome Mining ◽  
Fold Increase ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Automated Annotation ◽  
Fungal Genomes ◽  
Species Specific

Fungi are prolific producers of natural products, compounds which have had a large societal impact as pharmaceuticals, mycotoxins, and agrochemicals. Despite the availability of over 1,000 fungal genomes and several decades of compound discovery efforts from fungi, the biosynthetic gene clusters (BGCs) encoded by these genomes and the associated chemical space have yet to be analyzed systematically. Here, we provide detailed annotation and analyses of fungal biosynthetic and chemical space to enable genome mining and discovery of fungal natural products. Using 1,037 genomes from species across the fungal kingdom (e.g., Ascomycota, Basidiomycota, and non-Dikarya taxa), 36,399 predicted BGCs were organized into a network of 12,067 gene cluster families (GCFs). Anchoring these GCFs with reference BGCs enabled automated annotation of 2,026 BGCs with predicted metabolite scaffolds. We performed parallel analyses of the chemical repertoire of fungi, organizing 15,213 fungal compounds into 2,945 molecular families (MFs). The taxonomic landscape of fungal GCFs is largely species specific, though select families such as the equisetin GCF are present across vast phylogenetic distances with parallel diversifications in the GCF and MF. We compare these fungal datasets with a set of 5,453 bacterial genomes and their BGCs and 9,382 bacterial compounds, revealing dramatic differences between bacterial and fungal biosynthetic logic and chemical space. These genomics and cheminformatics analyses reveal the large extent to which fungal and bacterial sources represent distinct compound reservoirs. With a >10-fold increase in the number of interpreted strains and annotated BGCs, this work better regularizes the biosynthetic potential of fungi for rational compound discovery.

scholarly journals An Interpreted Atlas of Biosynthetic Gene Clusters from 1000 Fungal Genomes

2020 ◽  
Author(s):  
Matthew T. Robey ◽  
Lindsay K. Caesar ◽  
Milton T. Drott ◽  
Nancy P. Keller ◽  
Neil L. Kelleher
Keyword(s):  
Natural Products ◽  
Large Scale ◽  
Ad Hoc ◽  
Chemical Space ◽  
Genome Mining ◽  
Fold Increase ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Fungal Genomes

AbstractFungi are prolific producers of natural products, compounds which have had a large societal impact as pharmaceuticals, mycotoxins, and agrochemicals. Despite the availability of over 1000 fungal genomes and several decades of compound discovery efforts from fungi, the biosynthetic gene clusters (BGCs) encoded by these genomes and the associated chemical space have yet to be analyzed systematically. Here we provide detailed annotation and analyses of fungal biosynthetic and chemical space to enable genome mining and discovery of fungal natural products. Using 1037 genomes from species across the fungal kingdom (e.g., Ascomycota, Basidiomycota, and non-Dikarya taxa), 36,399 predicted BGCs were organized into a network of 12,067 gene cluster families (GCFs). Anchoring these GCFs with reference BGCs enabled automated annotation of 2,026 BGCs with predicted metabolite scaffolds. We performed parallel analyses of the chemical repertoire of Fungi, organizing 15,213 fungal compounds into 2,945 molecular families (MFs). The taxonomic landscape of fungal GCFs is largely species-specific, though select families such as the equisetin GCF are present across vast phylogenetic distances with parallel diversifications in the GCF and MF. We compare these fungal datasets with a set of 5,453 bacterial genomes and their BGCs and 9,382 bacterial compounds, revealing dramatic differences between bacterial and fungal biosynthetic logic and chemical space. These genomics and cheminformatics analyses reveal the large extent to which fungal and bacterial sources represent distinct compound reservoirs. With a >10-fold increase in the number of interpreted strains and annotated BGCs, this work better regularizes the biosynthetic potential of fungi for rational compound discovery.Significance StatementFungi represent an underexploited resource for new compounds with applications in the pharmaceutical and agriscience industries. Despite the availability of >1000 fungal genomes, our knowledge of the biosynthetic space encoded by these genomes is limited and ad hoc. We present results from systematically organizing the biosynthetic content of 1037 fungal genomes, providing a resource for data-driven genome mining and large-scale comparison of the genetic and molecular repertoires produced in fungi and compare to those present in bacteria.

Chemical Space and Biological Target Network of Anti-Inflammatory Natural Products

2018 ◽  
Vol 59 (1) ◽  
pp. 66-73 ◽  
Author(s):  
Ruihan Zhang ◽  
Jing Lin ◽  
Yan Zou ◽  
Xing-Jie Zhang ◽  
Wei-Lie Xiao
Keyword(s):  
Natural Products ◽  
Chemical Space ◽  
Target Network ◽  
Biological Target ◽  
Anti Inflammatory

Expanding the Natural Products Heterologous Expression Repertoire in the Model Cyanobacterium Anabaena sp. Strain PCC 7120: Production of Pendolmycin and Teleocidin B-4

2019 ◽  
Author(s):  
Patrick Videau ◽  
Kaitlyn Wells ◽  
Arun Singh ◽  
Jessie Eiting ◽  
Philip Proteau ◽  
...  
Keyword(s):  
Natural Products ◽  
Genome Mining ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Test Case ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Cyanobacterium Anabaena ◽  
Anabaena Sp ◽  
Pcc 7120

Cyanobacteria are prolific producers of natural products and genome mining has shown that many orphan biosynthetic gene clusters can be found in sequenced cyanobacterial genomes. New tools and methodologies are required to investigate these biosynthetic gene clusters and here we present the use of <i>Anabaena </i>sp. strain PCC 7120 as a host for combinatorial biosynthesis of natural products using the indolactam natural products (lyngbyatoxin A, pendolmycin, and teleocidin B-4) as a test case. We were able to successfully produce all three compounds using codon optimized genes from Actinobacteria. We also introduce a new plasmid backbone based on the native <i>Anabaena</i>7120 plasmid pCC7120ζ and show that production of teleocidin B-4 can be accomplished using a two-plasmid system, which can be introduced by co-conjugation.

scholarly journals Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 107
Author(s):  
Rafael de Felício ◽  
Patricia Ballone ◽  
Cristina Freitas Bazzano ◽  
Luiz F. G. Alves ◽  
Renata Sigrist ◽  
...  
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Natural Product ◽  
Deep Sea ◽  
Chemical Space ◽  
Bacterial Genome ◽  
Vast Number ◽  
Bacterial Metabolites ◽  
Laboratory Conditions ◽  
Deep Sea Bacteria

Bacterial genome sequencing has revealed a vast number of novel biosynthetic gene clusters (BGC) with potential to produce bioactive natural products. However, the biosynthesis of secondary metabolites by bacteria is often silenced under laboratory conditions, limiting the controlled expression of natural products. Here we describe an integrated methodology for the construction and screening of an elicited and pre-fractionated library of marine bacteria. In this pilot study, chemical elicitors were evaluated to mimic the natural environment and to induce the expression of cryptic BGCs in deep-sea bacteria. By integrating high-resolution untargeted metabolomics with cheminformatics analyses, it was possible to visualize, mine, identify and map the chemical and biological space of the elicited bacterial metabolites. The results show that elicited bacterial metabolites correspond to ~45% of the compounds produced under laboratory conditions. In addition, the elicited chemical space is novel (~70% of the elicited compounds) or concentrated in the chemical space of drugs. Fractionation of the crude extracts further evidenced minor compounds (~90% of the collection) and the detection of biological activity. This pilot work pinpoints strategies for constructing and evaluating chemically diverse bacterial natural product libraries towards the identification of novel bacterial metabolites in natural product-based drug discovery pipelines.

scholarly journals Genome Reduction and Secondary Metabolism of the Marine Sponge-Associated Cyanobacterium Leptothoe

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 298
Author(s):  
Despoina Konstantinou ◽  
Rafael V. Popin ◽  
David P. Fewer ◽  
Kaarina Sivonen ◽  
Spyros Gkelis
Keyword(s):  
Natural Products ◽  
Microbial Communities ◽  
Genomic Analysis ◽  
Gene Clusters ◽  
Marine Sponges ◽  
Genome Reduction ◽  
Extracellular Polysaccharides ◽  
Comparative Genomic ◽  
Symbiotic Relationships ◽  
Genes Encoding

Sponges form symbiotic relationships with diverse and abundant microbial communities. Cyanobacteria are among the most important members of the microbial communities that are associated with sponges. Here, we performed a genus-wide comparative genomic analysis of the newly described marine benthic cyanobacterial genus Leptothoe (Synechococcales). We obtained draft genomes from Le. kymatousa TAU-MAC 1615 and Le. spongobia TAU-MAC 1115, isolated from marine sponges. We identified five additional Leptothoe genomes, host-associated or free-living, using a phylogenomic approach, and the comparison of all genomes showed that the sponge-associated strains display features of a symbiotic lifestyle. Le. kymatousa and Le. spongobia have undergone genome reduction; they harbored considerably fewer genes encoding for (i) cofactors, vitamins, prosthetic groups, pigments, proteins, and amino acid biosynthesis; (ii) DNA repair; (iii) antioxidant enzymes; and (iv) biosynthesis of capsular and extracellular polysaccharides. They have also lost several genes related to chemotaxis and motility. Eukaryotic-like proteins, such as ankyrin repeats, playing important roles in sponge-symbiont interactions, were identified in sponge-associated Leptothoe genomes. The sponge-associated Leptothoe stains harbored biosynthetic gene clusters encoding novel natural products despite genome reduction. Comparisons of the biosynthetic capacities of Leptothoe with chemically rich cyanobacteria revealed that Leptothoe is another promising marine cyanobacterium for the biosynthesis of novel natural products.

scholarly journals MeFSAT: a curated natural product database specific to secondary metabolites of medicinal fungi

RSC Advances ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 2596-2607
Author(s):  
R. P. Vivek-Ananth ◽  
Ajaya Kumar Sahoo ◽  
Kavyaa Kumaravel ◽  
Karthikeyan Mohanraj ◽  
Areejit Samal
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Natural Product ◽  
Chemical Space ◽  
Therapeutic Uses ◽  
Medicinal Fungi ◽  
Fungal Natural Products

First dedicated manually curated resource on secondary metabolites and therapeutic uses of medicinal fungi. Cheminformatics based analysis of the chemical space of fungal natural products.

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