Building Natural Product Libraries Using Quantitative Clade-Based and Chemical Clustering Strategies

Anderson, Victoria M; Wendt, Karen L.; Najar, Fares Z.; McCall, Laura-Isobel; Cichewicz, Robert H.

doi:10.1128/msystems.00644-21

Cited by 5 publications

(7 citation statements)

References 72 publications

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“…Both methods were performed utilizing the online metabolomics database and processing servers provided by GNPS [ 17 ]. Based on prior literature, quantification values for each sample were subsequently normalized using rarefaction based on minimum intensity of 1e8 [ 48 ]. This data was further scaled for integration into the multi-omic feature set.…”

Section: Methodsmentioning

confidence: 99%

Location-specific signatures of Crohn’s disease at a multi-omics scale

et al. 2022

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Background Crohn’s disease (CD), an inflammatory bowel disease (IBD) subtype, results from pathologic interactions between host cells and its resident gut microbes. CD manifests in both isolated disease locations (ileum or colon) or a combination of locations (ileocolonic). To date, a comprehensive understanding of how isolated CD subtypes influence molecular profiles remains outstanding. To address this, we sought to define CD location signatures by leveraging a large cross-sectional feature set captured from the stool of over 200 IBD patients and healthy controls using metaproteomics, shotgun metagenomics, 16S rRNA sequencing, metabolomic profiling, and host genetics paired with clinical endoscopic assessments. Results Neither metagenomic nor host genetics alone distinguished CD location subtypes. In contrast, ileal and colonic CD were distinguished using mass spectrometry-based methods (metabolomics or metaproteomics) or a combined multi-omic feature set. This multi-omic feature set revealed colonic CD was strongly associated with neutrophil-related proteins. Additionally, colonic CD displayed a disease-severity-related association with Bacteroides vulgatus. Colonic CD and ulcerative colitis profiles harbored strikingly similar feature enrichments compared to ileal CD, including neutrophil-related protein enrichments. Compared to colonic CD, ileal CD profiles displayed increased primary and secondary bile acid levels and concomitant shifts in taxa with noted sensitivities such as Faecalibacterium prausnitzii or affinities for bile acid-rich environments, including Gammaproteobacteria and Blautia sp. Having shown robust molecular and microbial distinctions tied to CD locations, we leveraged these profiles to generate location-specific disease severity biomarkers that surpass the performance of Calprotectin. Conclusions When compared using multi-omics features, colonic- and ileal-isolated CD subtypes display striking differences that suggest separate location-specific pathologies. Colonic CD’s strong similarity to ulcerative colitis, including neutrophil and Bacteroides vulgatus involvement, is also evidence of a shared pathology for colonic-isolated IBD subtypes, while ileal CD maintains a unique, bile acid-driven profile. More broadly, this study demonstrates the power of multi-omics approaches for IBD biomarker discovery and elucidating the underlying biology.

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Section: Methodsmentioning

confidence: 99%

Location-specific signatures of Crohn’s disease at a multi-omics scale

et al. 2022

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“…This process, which requires painstaking efforts to repeatedly sterilize the cutting and sample manipulation tools (e.g., scissors, forceps, scalpels, dissection probes, pastry or pasta cutters, and other devices) necessitates that even experienced researchers are limited to processing roughly 4–6 samples per minute (these values are based on our personal experiences and have been further substantiated via communications with other mycologists). Since a single plant leaf may harbor dozens of symbionts, with some inhabiting only limited portions of the host tissue, it can become an arduous task to systematically sample even a single plant specimen, let alone explore large numbers of different plants. − Our team viewed such limitations as an opportunity to eliminate this bottleneck, which in turn would improve efforts to sample diverse assemblages of plants and secure the sizable numbers of isolates required for successful bioactive natural-product discovery efforts …”

Section: Resultsmentioning

confidence: 99%

“…45−47 Our team viewed such limitations as an opportunity to eliminate this bottleneck, which in turn would improve efforts to sample diverse assemblages of plants and secure the sizable numbers of isolates required for successful bioactive naturalproduct discovery efforts. 48 These challenges inspired our group to explore the use of laser-based precision cutting methods for preparing plant tissues because such an approach could in theory eliminate the need to physically touch a plant specimen once it has undergone an initial round of surface sterilization. After testing a variety of methods and devices, we found that a simple, hobby-grade, or light-duty commercial laser apparatus offered the best option for engineering a cost-effective plant specimen cutting tool.…”

Section: Development Of a Novel Endophyte Procurementmentioning

confidence: 99%

Persephacin Is a Broad-Spectrum Antifungal Aureobasidin Metabolite That Overcomes Intrinsic Resistance in Aspergillus fumigatus

Du,

Haldar,

King

et al. 2023

J. Nat. Prod.

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Fungi pose a persistent threat to humankind with worrying indications that emerging and re-emerging pathogens (e.g., Candida auris, Coccidioides spp., drug-resistant Aspergilli, and more) exhibit resistance to the limited number of approved antifungals. To address this problem, our team is exploring endophytic fungi as a resource for the discovery of new antifungal natural products. The rationale behind this decision is based on evidence that endophytes engage with plants in mutualistic relationships wherein some fungi actively participate by producing chemical defense measures that suppress pathogenic microorganisms. To improve the odds of bioactive metabolite discovery, we developed a new hands-free laser-cutting system capable of generating >50 plant samples per minute that, in turn, enabled our team to prepare and screen large numbers of endophytic fungi. One of the fungal isolates obtained in this way was identified as an Elsinoësp. that produced a unique aureobasidin analogue, persephacin (1). Some distinctive features of 1 are the absence of both phenylalanine residues combined with the incorporation of a novel amino acid residue, persephanine (9). Compound 1 exhibits potent antifungal effects against a large number of pathogenic yeast (including several clinical C. auris strains), as well as phylogenetically diverse filamentous fungi (e.g., Aspergillus f umigatus). In an ex vivo eye infection model, compound 1 outperformed standard-of-care treatments demonstrating the ability to suppress fluconazole-resistant Candida albicans and A. f umigatus at a concentration (0.1% solution) well below the clinically recommended levels used for fluconazole and natamycin (2% and 5% solutions, respectively). In 3D tissue models for acute dermal and ocular safety, 1 was found to be nontoxic and nonirritating at concentrations required to elicit antifungal activity. Natural product 1 appears to be a promising candidate for further investigation as a broad-spectrum antifungal capable of controlling a range of pathogens that negatively impact human, animal, and plant health.

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“…31 Complicating this matter further, it was shown that deep sampling of a single fungal genus could uncover surprisingly high levels of chemical diversity within a taxonomically restricted group. 32 Notwithstanding these and other efforts, some of the motives offered to support various microbial sourcing strategies for natural products discovery remain largely untested.…”

mentioning

confidence: 99%

“…This logic has been used to justify the pursuit of microbes and their natural products from a variety of curious and extraordinary locations. ,,− ,− However, recent efforts to compare microbially derived metabolites across two major biomes (i.e., terrestrial versus marine environments) revealed extensive overlap in the natural products being produced . Complicating this matter further, it was shown that deep sampling of a single fungal genus could uncover surprisingly high levels of chemical diversity within a taxonomically restricted group . Notwithstanding these and other efforts, some of the motives offered to support various microbial sourcing strategies for natural products discovery remain largely untested.…”

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confidence: 99%

Assessing Microbial Metabolic and Biological Diversity to Inform Natural Product Library Assembly

et al. 2022

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The pressing need for novel chemical matter to support bioactive compound discovery has led natural product researchers to explore a wide range of source organisms and environments. One of the implicit guiding principles behind those efforts is the notion that sampling different environments is critical to accessing unique natural products. This idea was tested by comparing fungi from disparate biomes: aquatic sediments from Lake Michigan (USA) and terrestrial samples taken from the surrounding soils. Matched sets of Penicillium brevicompactum, Penicillium expansum, and Penicillium oxalicum from the two source environments were compared, revealing modest differences in physiological performance and chemical output. Analysis of LC-MS/MS-derived molecular feature data showed no source-dependent differences in chemical richness. High levels of scaffold homogeneity were also observed with 78−83% of scaffolds shared among the terrestrial and aquatic Penicillium spp. isolates. A comparison of the culturable fungi from the two biomes indicated that certain genera were more strongly associated with aquatic sediments (e.g., Trichoderma, Pseudeurotium, Cladosporium, and Preussia) versus the surrounding terrestrial environment (e.g., Fusarium, Pseudogymnoascus, Humicola, and Acremonium). Taken together, these results suggest that focusing efforts on sampling the microbial resources that are unique to an environment may have a more pronounced effect on enhancing the sought-after natural product diversity needed for chemical discovery and screening collections.

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Building Natural Product Libraries Using Quantitative Clade-Based and Chemical Clustering Strategies

Abstract: Natural product drug discovery efforts rely on libraries of organisms to provide access to diverse pools of compounds. Actionable strategies to rationally maximize chemical diversity, rather than relying on serendipity, can add value to such efforts.

Cited by 5 publications

References 72 publications

Location-specific signatures of Crohn’s disease at a multi-omics scale

Location-specific signatures of Crohn’s disease at a multi-omics scale

Persephacin Is a Broad-Spectrum Antifungal Aureobasidin Metabolite That Overcomes Intrinsic Resistance in Aspergillus fumigatus

Assessing Microbial Metabolic and Biological Diversity to Inform Natural Product Library Assembly

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