scholarly journals Integration of high-content screening and untargeted metabolomics for comprehensive functional annotation of natural product libraries

2015 ◽  
Vol 112 (39) ◽  
pp. 11999-12004 ◽  
Author(s):  
Kenji L. Kurita ◽  
Emerson Glassey ◽  
Roger G. Linington
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Chemical Properties ◽  
Untargeted Metabolomics ◽  
Bioactive Metabolites ◽  
Discovery Process ◽  
Bioactive Constituents ◽  
Modes Of Action ◽  
New Family ◽  
Natural Products Discovery

Traditional natural products discovery using a combination of live/dead screening followed by iterative bioassay-guided fractionation affords no information about compound structure or mode of action until late in the discovery process. This leads to high rates of rediscovery and low probabilities of finding compounds with unique biological and/or chemical properties. By integrating image-based phenotypic screening in HeLa cells with high-resolution untargeted metabolomics analysis, we have developed a new platform, termed Compound Activity Mapping, that is capable of directly predicting the identities and modes of action of bioactive constituents for any complex natural product extract library. This new tool can be used to rapidly identify novel bioactive constituents and provide predictions of compound modes of action directly from primary screening data. This approach inverts the natural products discovery process from the existing ‟grind and find” model to a targeted, hypothesis-driven discovery model where the chemical features and biological function of bioactive metabolites are known early in the screening workflow, and lead compounds can be rationally selected based on biological and/or chemical novelty. We demonstrate the utility of the Compound Activity Mapping platform by combining 10,977 mass spectral features and 58,032 biological measurements from a library of 234 natural products extracts and integrating these two datasets to identify 13 clusters of fractions containing 11 known compound families and four new compounds. Using Compound Activity Mapping we discovered the quinocinnolinomycins, a new family of natural products with a unique carbon skeleton that cause endoplasmic reticulum stress.

scholarly journals High-Throughput Functional Annotation of Natural Products by Integrated Activity Profiling

2019 ◽  
Author(s):  
Suzie K. Hight ◽  
Kenji L. Kurita ◽  
Elizabeth A. McMillan ◽  
Walter Bray ◽  
Trevor N. Clark ◽  
...  
Keyword(s):  
Natural Products ◽  
Untargeted Metabolomics ◽  
Bioactive Metabolites ◽  
Integrative Approach ◽  
Expression Platform ◽  
Gene Expression Platform ◽  
Powerful Approach ◽  
Natural Products Discovery ◽  
Cytological Profiling ◽  
Screening Approaches

AbstractDetermining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform FUSION. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using KS-tests to compare in-class to out-of-class similarity, we found that SNF resulted in improved power to correctly assign MOA over either dataset alone. Furthermore, we integrated untargeted metabolomics of complex natural product fractions to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as powerful approach for advancing natural products drug discovery.

scholarly journals Total Synthesis of the Reported Structure of Cahuitamycin A

2020 ◽  
Author(s):  
Justin Shapiro ◽  
Savannah Post ◽  
William Wuest
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Natural Product ◽  
Twelve Step ◽  
Target Compound ◽  
New Family ◽  
Iron Trafficking ◽  
Linear Sequence ◽  
Alternative Structure ◽  
Synthetic Target

In a 2016 screen of natural product extracts a new family of natural products, the cahuitamycins, was discovered and found to inhibit the formation of biofilms in the human pathogen <i>Acinetobacter baumannii</i>. The molecules contain an unusual piperazate residue that raises structure/function and biosynthesis questions and resemble iron-trafficking virulence factors from <i>A. baumannii</i>, suggesting a connection between metal homeostasis and biofilm-mediated pathogenicity. Here we disclose the first total synthesis of the reported structure of cahuitamycin A in a twelve-step longest linear sequence and 18% overall yield. Comparison of spectral data of the authentic natural product and synthetic target compound demonstrate that the reported structure is distinct from the isolated metabolite. Herein, we propose an alternative structure to reconcile our findings with the isolation report, setting the stage for future synthetic and biochemical investigations of an important class of natural products.

Detection of pharmacologically active natural products using ecology. Selected examples from Indopacific marine invertebrates and sponge-derived fungi

2003 ◽  
Vol 75 (2-3) ◽  
pp. 343-352 ◽  
Author(s):  
P. Proksch ◽  
R. Ebel ◽  
R. A. Edrada ◽  
P. Schupp ◽  
W. H. Lin ◽  
...  
Keyword(s):  
Natural Products ◽  
Marine Invertebrates ◽  
Marine Sponges ◽  
Bioactive Metabolites ◽  
Marine Biodiversity ◽  
Marine Microorganisms ◽  
Bioactive Constituents ◽  
Isolation And Identification ◽  
Bioactive Natural Products ◽  
Pharmacologically Active

This review article presents our group's recent research findings with regard to bioactive natural products from marine sponges and tunicates, as well as from sponge derived fungi. The organisms discussed originate in the Indopacific region, which has an exceptionally rich marine biodiversity. Major topics that are covered in our review include the chemical ecology of sponges, focusing on defense against fishes, as well as the isolation and identification of new bioactive constituents from sponges and tunicates. Sponge derived fungi are introduced as an emerging source for new bioactive metabolites, reflecting the currently growing interest in natural products from marine microorganisms.

scholarly journals Total Synthesis of the Reported Structure of Cahuitamycin A

2020 ◽  
Author(s):  
Justin Shapiro ◽  
Savannah Post ◽  
William Wuest
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Natural Product ◽  
Twelve Step ◽  
Target Compound ◽  
New Family ◽  
Iron Trafficking ◽  
Linear Sequence ◽  
Alternative Structure ◽  
Synthetic Target

In a 2016 screen of natural product extracts a new family of natural products, the cahuitamycins, was discovered and found to inhibit the formation of biofilms in the human pathogen <i>Acinetobacter baumannii</i>. The molecules contain an unusual piperazate residue that raises structure/function and biosynthesis questions and resemble iron-trafficking virulence factors from <i>A. baumannii</i>, suggesting a connection between metal homeostasis and biofilm-mediated pathogenicity. Here we disclose the first total synthesis of the reported structure of cahuitamycin A in a twelve-step longest linear sequence and 18% overall yield. Comparison of spectral data of the authentic natural product and synthetic target compound demonstrate that the reported structure is distinct from the isolated metabolite. Herein, we propose an alternative structure to reconcile our findings with the isolation report, setting the stage for future synthetic and biochemical investigations of an important class of natural products.

scholarly journals Discovery and biosynthesis of clostyrylpyrones from the obligate anaerobe Clostridium roseum

2020 ◽  
Author(s):  
Jeffrey S Li ◽  
Yongle Du ◽  
Di Gu ◽  
Wenlong Cai ◽  
Allison Green ◽  
...  
Keyword(s):  
Natural Products ◽  
Heterologous Expression ◽  
Natural Product ◽  
Biochemical Analysis ◽  
Polyketide Synthase ◽  
Gene Knockout ◽  
Anaerobic Bacteria ◽  
Obligate Anaerobe ◽  
New Family ◽  
Expression Studies

ABSTRACTAnaerobic bacteria are a promising new source for natural product discovery. Examination of extracts from the obligate anaerobe Clostridium roseum led to discovery of a new family of natural products, the clostyrylpyrones. The polyketide synthase-based biosynthetic mechanism of clostyrylpyrones is further proposed based on bioinformatic, gene knockout, biochemical analysis and heterologous expression studies.

scholarly journals Imaging mass spectrometry for natural products discovery: a review of ionization methods

2020 ◽  
Vol 37 (2) ◽  
pp. 150-162 ◽  
Author(s):  
Joseph E. Spraker ◽  
Gordon T. Luu ◽  
Laura M. Sanchez
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Natural Product ◽  
Imaging Mass Spectrometry ◽  
Natural Product Discovery ◽  
Ionization Sources ◽  
Natural Products Discovery ◽  
Ionization Methods

This mini review discusses advantages, limitations, and examples of different mass spectrometry ionization sources applicable to natural product discovery workflows.

scholarly journals Recent developments of tools for genome and metabolome studies in basidiomycete fungi and their application to natural product research

Biology Open ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. bio056010
Author(s):  
Fabrizio Alberti ◽  
Saraa Kaleem ◽  
Jack A. Weaver
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Gene Clusters ◽  
Bioactive Metabolites ◽  
Network Analyses ◽  
Natural Product Research ◽  
Technological Advances ◽  
Long Read ◽  
Recent Developments ◽  
Basidiomycete Fungi

ABSTRACTBasidiomycota are a large and diverse phylum of fungi. They can make bioactive metabolites that are used or have inspired the synthesis of antibiotics and agrochemicals. Terpenoids are the most abundant class of natural products encountered in this taxon. Other natural product classes have been described, including polyketides, peptides, and indole alkaloids. The discovery and study of natural products made by basidiomycete fungi has so far been hampered by several factors, which include their slow growth and complex genome architecture. Recent developments of tools for genome and metabolome studies are allowing researchers to more easily tackle the secondary metabolome of basidiomycete fungi. Inexpensive long-read whole-genome sequencing enables the assembly of high-quality genomes, improving the scaffold upon which natural product gene clusters can be predicted. CRISPR/Cas9-based engineering of basidiomycete fungi has been described and will have an important role in linking natural products to their genetic determinants. Platforms for the heterologous expression of basidiomycete genes and gene clusters have been developed, enabling natural product biosynthesis studies. Molecular network analyses and publicly available natural product databases facilitate data dereplication and natural product characterisation. These technological advances combined are prompting a revived interest in natural product discovery from basidiomycete fungi.This article has an associated Future Leader to Watch interview with the first author of the paper.

Dereplication: racing to speed up the natural products discovery process

2015 ◽  
Vol 32 (6) ◽  
pp. 779-810 ◽  
Author(s):  
Susana P. Gaudêncio ◽  
Florbela Pereira
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Major Bottleneck ◽  
Speed Up ◽  
Natural Products Discovery

To alleviate the dereplication holdup, which is a major bottleneck in natural products discovery, scientists have been conducting their research efforts to add tools to their “bag of tricks” aiming to achieve faster, more accurate and efficient ways to accelerate the pace of the drug discovery process.

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