Bioactivity-driven fungal metabologenomics identifies antiproliferative stemphone analogs and their biosynthetic gene cluster.

Introduction: Fungi biosynthesize chemically diverse secondary metabolites with a wide range of biological activities. Natural product scientists have increasingly turned towards bioinformatics approaches, combining metabolomics and genomics to target secondary metabolites and their biosynthetic machinery. We recently applied an integrated metabologenomics workflow to 110 fungi and identified more than 230 high-confidence linkages between metabolites and their biosynthetic pathways.

Interaction Metabolomics to Discover Synergists in Natural Product Mixtures.

Mass spectrometry metabolomics has become increasingly popular as an integral aspect of studies to identify active compounds from natural product mixtures. Classical metabolomics data analysis approaches do not consider the possibility that interactions (such as synergy) could occur between mixture components. With this study, we developed "interaction metabolomics" to overcome this limitation.

Correlative metabologenomics of 110 fungi reveals metabolite-gene cluster pairs.

Natural products research increasingly applies -omics technologies to guide molecular discovery. While the combined analysis of genomic and metabolomic datasets has proved valuable for identifying natural products and their biosynthetic gene clusters (BGCs) in bacteria, this integrated approach lacks application to fungi. Because fungi are hyper-diverse and underexplored for new chemistry and bioactivities, we created a linked genomics-metabolomics dataset for 110 Ascomycetes, and optimized both gene cluster family (GCF) networking parameters and correlation-based scoring for pairing fungal natural products with their BGCs.

Chalcones from Angelica keiskei (ashitaba) inhibit key Zika virus replication proteins.

Zika virus (ZIKV) is a dangerous human pathogen and no antiviral drugs have been approved to date. The chalcones are a group of small molecules that are found in a number of different plants, including Angelica keiskei Koidzumi, also known as ashitaba. To examine chalcone anti-ZIKV activity, three chalcones, 4-hydroxyderricin (4HD), xanthoangelol (XA), and xanthoangelol-E (XA-E), were purified from a methanol-ethyl acetate extract from A.

Metabolomics and genomics in natural products research: complementary tools for targeting new chemical entities.

Covering: 2010 to 2021Organisms in nature have evolved into proficient synthetic chemists, utilizing specialized enzymatic machinery to biosynthesize an inspiring diversity of secondary metabolites. Often serving to boost competitive advantage for their producers, these secondary metabolites have widespread human impacts as antibiotics, anti-inflammatories, and antifungal drugs. The natural products discovery field has begun a shift away from traditional activity-guided approaches and is beginning to take advantage of increasingly available metabolomics and genomics datasets to explore undiscovered chemical space.

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

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.

In the fungus where it happens: History and future propelling Aspergillus nidulans as the archetype of natural products research.

In 1990 the first fungal secondary metabolite biosynthetic gene was cloned in Aspergillus nidulans. Thirty years later, >30 biosynthetic gene clusters (BGCs) have been linked to specific natural products in this one fungal species. While impressive, over half of the BGCs in A.

Heterologous Expression of the Unusual Terreazepine Biosynthetic Gene Cluster Reveals a Promising Approach for Identifying New Chemical Scaffolds.

Advances in genome sequencing have revitalized natural product discovery efforts, revealing the untapped biosynthetic potential of fungi. While the volume of genomic data continues to expand, discovery efforts are slowed due to the time-consuming nature of experiments required to characterize new molecules. To direct efforts toward uncharacterized biosynthetic gene clusters most likely to encode novel chemical scaffolds, we took advantage of comparative metabolomics and heterologous gene expression using fungal artificial chromosomes (FACs).

Targeted and untargeted analysis of secondary metabolites to monitor growth and quorum sensing inhibition for methicillin-resistant Staphylococcus aureus (MRSA).

Drug resistant infections are an increasing problem world-wide, responsible for an estimated 700,000 annual mortalities. The use of antibiotics to treat such infections has resulted in the development of resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). One potential alternative strategy for treating drug resistant bacterial infections is to inhibit the production of toxins, thereby making the bacteria less harmful to the host, a so called "anti-virulence" approach.

Chemical Evaluation of the Effects of Storage Conditions on the Botanical Goldenseal using Marker-based and Metabolomics Approaches.

commonly known as goldenseal, is a botanical native to the southeastern United States that has been used for the treatment of infection. The activity of goldenseal is often attributed to the presence of alkaloids (cyclic, nitrogen-containing compounds) present within its roots. Chemical components of botanical supplements like goldenseal may face degradation if not stored properly.

Processing, Export, and Identification of Novel Linear Peptides from Staphylococcus aureus.

can colonize the human host and cause a variety of superficial and invasive infections. The success of as a pathogen derives from its ability to modulate its virulence through the release, sensing of and response to cyclic signaling peptides. Here we provide, for the first time, evidence that processes and secretes small linear peptides through a specialized pathway that converts a lipoprotein leader into an extracellular peptide signal.

Simplify: A Mass Spectrometry Metabolomics Approach to Identify Additives and Synergists from Complex Mixtures.

In fields ranging from environmental toxicology to drug discovery, it is critical to identify how multiple chemical compounds interact to perturb biological systems. Isolation-based approaches fail to incorporate multiconstituent interactions, such as synergy. We have developed an approach called "Simplify", which identifies mixture constituents that interact to achieve biological effects.

Synergy and antagonism in natural product extracts: when 1 + 1 does not equal 2.

Covering: 2000 to 2019 According to a 2012 survey from the Centers for Disease Control and Prevention, approximately 18% of the U.S. population uses natural products (including plant-based or botanical preparations) for treatment or prevention of disease.

Phytochemical Analysis and Antimicrobial Efficacy of against Extensively Drug-Resistant .

The antibiotic resistant threat is continuing to grow, due in part to the overuse of antibiotics in livestock feed. Many nations in Europe have banned the use of antibiotics in feed, leading to higher rates of infection in livestock animals and reduced productivity for the food market. Increasingly, researchers are looking into the efficacy of phytopreparations to replace antibiotics in feed, allowing for increased animal health without the development of resistance.

Opportunities and Limitations for Untargeted Mass Spectrometry Metabolomics to Identify Biologically Active Constituents in Complex Natural Product Mixtures.

Compounds derived from natural sources represent the majority of small-molecule drugs utilized today. Plants, owing to their complex biosynthetic pathways, are poised to synthesize diverse secondary metabolites that selectively target biological macromolecules. Despite the vast chemical landscape of botanicals, drug discovery programs from these sources have diminished due to the costly and time-consuming nature of standard practices and high rates of compound rediscovery.

Mapping the Fungal Battlefield: Using Chemistry and Deletion Mutants to Monitor Interspecific Chemical Interactions Between Fungi.

Fungi grow in competitive environments, and to cope, they have evolved strategies, such as the ability to produce a wide range of secondary metabolites. This begs two related questions. First, how do secondary metabolites influence fungal ecology and interspecific interactions? Second, can these interspecific interactions provide a way to "see" how fungi respond, chemically, within a competitive environment? To evaluate these, and to gain insight into the secondary metabolic arsenal fungi possess, we co-cultured , a genetically tractable fungus that produces a suite of mycotoxins, with , a fungus that produces the fungistatic compound and FDA-approved drug, griseofulvin.

Analytical methods for the study of bioactive compounds from medicinally used Echinacea species.

Echinacea purpurea (L.) Moench, Echinacea angustifolia DC. var.

Hierarchical cluster analysis of technical replicates to identify interferents in untargeted mass spectrometry metabolomics.

Mass spectral data sets often contain experimental artefacts, and data filtering prior to statistical analysis is crucial to extract reliable information. This is particularly true in untargeted metabolomics analyses, where the analyte(s) of interest are not known a priori. It is often assumed that chemical interferents (i.

Integration of Biochemometrics and Molecular Networking to Identify Antimicrobials in Angelica keiskei.

Botanical medicines have been utilized for centuries, but it remains challenging to identify bioactive constituents from complex botanical extracts. Bioassay-guided fractionation is often biased toward abundant or easily isolatable compounds. To comprehensively evaluate active botanical mixtures, methods that allow for the prioritization of active compounds are needed.

A Review of the Medicinal Uses and Pharmacology of Ashitaba.

Angelica keiskei Koidzumi, or ashitaba, is a popular botanical medicine in Japan containing diverse bioactive components including prenylated chalcones, linear and angular coumarins, and flavanones. This review provides an overview of the current knowledge of ashitaba metabolites and their biological activities to prioritize future studies. Ashitaba is purported to possess cytotoxic, antidiabetic, antioxidative, anti-inflammatory, antihypertensive, and antimicrobial properties.