New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in <i>Aspergillus nidulans</i>

Henke, Matthew T.; Soukup, Alexandra A.; Goering, Anthony W.; McClure, Ryan A.; Thomson, Regan J.; Keller, Nancy P.; Kelleher, Neil L.

doi:10.1021/acschembio.6b00398

Cited by 48 publications

(39 citation statements)

References 37 publications

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“…An alternative strategy employs, in a single growth medium, defined chemical or biological agents that model ecological and environmental stimuli. Discrete stimuli found to elicit natural product production include histone deacetylase inhibitors (10,11), exposure to subinhibitory levels of antibiotics (12)(13)(14), selection for spontaneous antibiotic resistance (15,16), low-level metal exposure (17), and mixed microbial culture (18,19). The finding that variations in discrete chemical and biological stimuli can alter secondary metabolite production is consistent with the hypothesis that the role of most natural products is to respond to environmental interactions.…”

supporting

confidence: 67%

Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli

Covington

Spraggins

Yñigez-Gutierrez

et al. 2018

Appl Environ Microbiol

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Microorganisms within microbial communities respond to environmental challenges by producing biologically active secondary metabolites, yet the majority of these small molecules remain unidentified. We have previously demonstrated that secondary metabolite biosynthesis in actinomycetes can be activated by model environmental chemical and biological stimuli, and metabolites can be identified by comparative metabolomics analyses between stimuli conditions. Herein, we survey the secondary metabolite productivity of a group of 20 phylogenetically diverse actinobacteria isolated from hypogean (cave) environments by applying a battery of stimuli consisting of exposure to antibiotics, metals, and mixed microbial culture. Comparative metabolomics was used to reveal secondary metabolite responses from stimuli. These analyses revealed substantial changes in global metabolomic dynamics with over 30 % of metabolomic features increasing more than 10-fold under at least one stimulus condition. Selected features were isolated and identified via NMR, revealing several known secondary metabolite families including the tetarimycins, aloesaponarins, hypogeamicins, actinomycins, and propeptins. One prioritized metabolite was identified to be a previously unreported aminopolyol polyketide, funisamine, produced by a cave isolate when exposed to mixed culture. The production of funisamine was most significantly increased in mixed culture with sp. The biosynthetic gene cluster responsible for the production of funisamine was identified via genomic sequencing of the producing strain, sp. KDCAGE35, which facilitated deduction of its biosynthesis. Together, these data demonstrate that comparative metabolomics can reveal the stimulus-induced production of natural products from diverse microbial phylogenies. Microbial secondary metabolites are an important source of biologically active and therapeutically relevant small molecules. However, much of this active molecular diversity is challenging to access due to low production levels or difficulty in discerning secondary metabolites within complex microbial extracts prior to isolation. Herein we demonstrate that ecological stimuli increase secondary metabolite production in phylogenetically diverse actinobacteria isolated from understudied hypogean environments. Additionally, we show that comparative metabolomics linking stimuli to metabolite response data can effectively reveal secondary metabolites within complex biological extracts. This approach highlighted secondary metabolites in almost all observed natural product classes, including low abundance analogs of biologically relevant metabolites, as well as a new linear aminopolyol polyketide, funisamine. This study demonstrates the generality of activating stimuli to potentiate secondary metabolite production across diverse actinobacterial genera.

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supporting

confidence: 67%

Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli

Covington

Spraggins

Yñigez-Gutierrez

et al. 2018

Appl Environ Microbiol

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“…6 In a natural product molecular network, these clusters represent molecular families (MFs) putatively synthesized by gene cluster families (GCFs). 7 Molecular networking is a powerful approach that has advanced several natural product-related research projects involving dereplication and quantification, 8 discovery, 9 biosynthesis, 10 and chemical ecology. 11 It has also been integrated as a central component of the Global Natural Products Social (GNPS) molecular networking platform, where dereplication is performed against a large, community-acquired reference library of spectra.…”

mentioning

confidence: 99%

Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols

Crüsemann¹,

O’Neill²,

Larson³

et al. 2016

J. Nat. Prod.

112

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In order to expedite the rapid and efficient discovery and isolation of novel specialized metabolites, whilst minimizing the waste of resources on rediscovery of known compounds, it is crucial to develop efficient approaches for strain prioritization, rapid dereplication, and the assessment of favored cultivation and extraction conditions. Herein we interrogated bacterial strains by systematically evaluating cultivation and extraction parameters with LC-MS/MS analysis and subsequent dereplication through the Global Natural Product Social Molecular Networking (GNPS) platform. The developed method is fast, requiring minimal time and sample material, and is compatible with high throughput extract analysis, thereby streamlining strain prioritization and evaluation of culturing parameters. With this approach, we analyzed 146 marine Salinispora and Streptomyces strains that were grown and extracted using multiple different protocols. In total, 603 samples were analyzed, generating approximately 1.8 million mass spectra. We constructed a comprehensive molecular network and identified 15 molecular families of diverse natural products and their analogues. The size and breadth of this network shows statistically supported trends in molecular diversity when comparing growth and extraction conditions. The network provides an extensive survey of the biosynthetic capacity of the strain collection and a method to compare strains based on the variety and novelty of their metabolites. This approach allows us to quickly identify patterns in metabolite production that can be linked to taxonomy, culture conditions, and extraction methods, as well as informing the most valuable growth and extraction conditions.

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“…However, when using metabolomics to study the knockdown of the HDAC rpdA in Aspergillus nidulans, a simultaneous 100-fold increase in the relative expression levels of 61 compounds and 100-fold decrease in 47 compounds was observed, indicating the unpredictable nature of using pleiotropic strategies [14]. Further investigation revealed that A. nidulans produced several fellutamides with proteasome inhibition and antibiotic activities, and subsequent work uncovered a new class of lipopeptides, the aspercryptins [15].…”

Section: Manipulating Global Transcriptionmentioning

confidence: 99%

Strategies for Engineering Natural Product Biosynthesis in Fungi

Skellam

2019

Trends in Biotechnology

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Fungi are a prolific source of bioactive compounds, some of which have been developed as essential medicines and life-enhancing drugs. Genome sequencing has revealed that fungi have the potential to produce considerably more natural products (NPs) than are typically observed in the laboratory. Recently, there have been significant advances in the identification, understanding, and engineering of fungal biosynthetic gene clusters (BGCs). This review briefly describes examples of the engineering of fungal NP biosynthesis at the global, pathway, and enzyme level using in vivo and in vitro approaches and refers to the range and scale of heterologous expression systems available, developments in combinatorial biosynthesis, progress in understanding how fungal BGCs are regulated, and the applications of these novel biosynthetic enzymes as biocatalysts. Fungal NPs and Human Health NPs (see Glossary) or NP derivatives represented 25% of all FDA-approved drugs in the years spanning 1981 to 2014 [1]. Fungi are prolific producers of some of these important drugs, such as antibiotics (e.g., penicillin, pleuromutilin), cholesterol-lowering drugs (e.g., lovastatin, compactin), and immunosuppressants (e.g., mycophenolic acid, cyclosporine). Fungal NPs have many biological activities, ranging from carcinogens (e.g., aflatoxins), deadly toxins (e.g., a-amanitin), and industrial fungicides (e.g., strobilurin) to food colorants (e.g., azaphilones), hormones (e.g., gibberellin), and psychedelics (e.g., psilocybin) [2,3]. In nature, these NPs serve to protect fungi from predators (e.g., insects), UV radiation, and competition from other microorganisms and have evolved to secure their survival in niche habitats; they just happen to have had a profound effect on human health. The broad spectrum of biological activities reflects their structural diversity, which arises from their biosynthetic classification (e.g., polyketides, peptides, terpenes, alkaloids) (Figure 1). The complexity of fungal secondary metabolism presents numerous challenges for traditional drug discovery. Fungi often produce NPs at very low levels or in response to specific environmental cues that are difficult to reproduce in the laboratory [4]. The prominence of NPs in the pharmaceutical industry and re-emerging interest in NPs as lead structures in drug discovery [5] require methods to engineer improved NP analogs and activate silent biosynthetic pathways. In recent years there have been substantial advances in strategies for engineering fungal NP biosynthesis (Figure 2, Key Figure), which are highlighted in this review. These strategies can be divided into three broad categories: (i) inducing global transcriptional perturbations (e.g., through epigenetic modifications or the overexpression of global transcriptional regulators), which effectively 'awakens' the biosynthetic machinery and often affects multiple pathways resulting in the production of a variety of NPs, but is unpredictable and difficult to control Highlights

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New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans

Cited by 48 publications

References 37 publications

Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli

Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli

Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols

Strategies for Engineering Natural Product Biosynthesis in Fungi

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