Publications by authors named "Katherine R Duncan"

14 Publications

  • Page 1 of 1

Ranking microbial metabolomic and genomic links in the NPLinker framework using complementary scoring functions.

PLoS Comput Biol 2021 May 4;17(5):e1008920. Epub 2021 May 4.

School of Computing Science, University of Glasgow, Glasgow, United Kingdom.

Specialised metabolites from microbial sources are well-known for their wide range of biomedical applications, particularly as antibiotics. When mining paired genomic and metabolomic data sets for novel specialised metabolites, establishing links between Biosynthetic Gene Clusters (BGCs) and metabolites represents a promising way of finding such novel chemistry. However, due to the lack of detailed biosynthetic knowledge for the majority of predicted BGCs, and the large number of possible combinations, this is not a simple task. This problem is becoming ever more pressing with the increased availability of paired omics data sets. Current tools are not effective at identifying valid links automatically, and manual verification is a considerable bottleneck in natural product research. We demonstrate that using multiple link-scoring functions together makes it easier to prioritise true links relative to others. Based on standardising a commonly used score, we introduce a new, more effective score, and introduce a novel score using an Input-Output Kernel Regression approach. Finally, we present NPLinker, a software framework to link genomic and metabolomic data. Results are verified using publicly available data sets that include validated links.
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http://dx.doi.org/10.1371/journal.pcbi.1008920DOI Listing
May 2021

Comparative Metabologenomics Analysis of Polar Actinomycetes.

Mar Drugs 2021 Feb 10;19(2). Epub 2021 Feb 10.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.

Biosynthetic and chemical datasets are the two major pillars for microbial drug discovery in the era. Despite the advancement of analysis tools and platforms for multi-strain metabolomics and genomics, linking these information sources remains a considerable bottleneck in strain prioritisation and natural product discovery. In this study, molecular networking of the 100 metabolite extracts derived from applying the OSMAC approach to 25 Polar bacterial strains, showed growth media specificity and potential chemical novelty was suggested. Moreover, the metabolite extracts were screened for antibacterial activity and promising selective bioactivity against drug-persistent pathogens such as and was observed. Genome sequencing data were combined with metabolomics experiments in the recently developed computational approach, NPLinker, which was used to link BGC and molecular features to prioritise strains for further investigation based on biosynthetic and chemical information. Herein, we putatively identified the known metabolites ectoine and chrloramphenicol which, through NPLinker, were linked to their associated BGCs. The metabologenomics approach followed in this study can potentially be applied to any large microbial datasets for accelerating the discovery of new (bioactive) specialised metabolites.
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http://dx.doi.org/10.3390/md19020103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916644PMC
February 2021

Exploring the Chemical Space of Macro- and Micro-Algae Using Comparative Metabolomics.

Microorganisms 2021 Feb 3;9(2). Epub 2021 Feb 3.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.

With more than 156,000 described species, eukaryotic algae (both macro- and micro-algae) are a rich source of biological diversity, however their chemical diversity remains largely unexplored. Specialised metabolites with promising biological activities have been widely reported for seaweeds, and more recently extracts from microalgae have exhibited activity in anticancer, antimicrobial, and antioxidant screens. However, we are still missing critical information on the distinction of chemical profiles between macro- and microalgae, as well as the chemical space these metabolites cover. This study has used an untargeted comparative metabolomics approach to explore the chemical diversity of seven seaweeds and 36 microalgal strains. A total of 1390 liquid chromatography-mass spectrometry (LC-MS) features were detected, representing small organic algal metabolites, with no overlap between the seaweeds and microalgae. An in-depth analysis of four strains shows that environmental factors may play a larger role than phylogeny when classifying their metabolomic profiles.
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http://dx.doi.org/10.3390/microorganisms9020311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913273PMC
February 2021

Linking genomics and metabolomics to chart specialized metabolic diversity.

Chem Soc Rev 2020 Jun 12;49(11):3297-3314. Epub 2020 May 12.

Bioinformatics Group, Wageningen University, Wageningen, The Netherlands.

Microbial and plant specialized metabolites constitute an immense chemical diversity, and play key roles in mediating ecological interactions between organisms. Also referred to as natural products, they have been widely applied in medicine, agriculture, cosmetic and food industries. Traditionally, the main discovery strategies have centered around the use of activity-guided fractionation of metabolite extracts. Increasingly, omics data is being used to complement this, as it has the potential to reduce rediscovery rates, guide experimental work towards the most promising metabolites, and identify enzymatic pathways that enable their biosynthetic production. In recent years, genomic and metabolomic analyses of specialized metabolic diversity have been scaled up to study thousands of samples simultaneously. Here, we survey data analysis technologies that facilitate the effective exploration of large genomic and metabolomic datasets, and discuss various emerging strategies to integrate these two types of omics data in order to further accelerate discovery.
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http://dx.doi.org/10.1039/d0cs00162gDOI Listing
June 2020

The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery.

ACS Cent Sci 2019 Nov 14;5(11):1824-1833. Epub 2019 Nov 14.

Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii 96822, United States.

Despite rapid evolution in the area of microbial natural products chemistry, there is currently no open access database containing all microbially produced natural product structures. Lack of availability of these data is preventing the implementation of new technologies in natural products science. Specifically, development of new computational strategies for compound characterization and identification are being hampered by the lack of a comprehensive database of known compounds against which to compare experimental data. The creation of an open access, community-maintained database of microbial natural product structures would enable the development of new technologies in natural products discovery and improve the interoperability of existing natural products data resources. However, these data are spread unevenly throughout the historical scientific literature, including both journal articles and international patents. These documents have no standard format, are often not digitized as machine readable text, and are not publicly available. Further, none of these documents have associated structure files (e.g., MOL, InChI, or SMILES), instead containing images of structures. This makes extraction and formatting of relevant natural products data a formidable challenge. Using a combination of manual curation and automated data mining approaches we have created a database of microbial natural products (The Natural Products Atlas, www.npatlas.org) that includes 24 594 compounds and contains referenced data for structure, compound names, source organisms, isolation references, total syntheses, and instances of structural reassignment. This database is accompanied by an interactive web portal that permits searching by structure, substructure, and physical properties. The Web site also provides mechanisms for visualizing natural products chemical space and dashboards for displaying author and discovery timeline data. These interactive tools offer a powerful knowledge base for natural products discovery with a central interface for structure and property-based searching and presents new viewpoints on structural diversity in natural products. The Natural Products Atlas has been developed under FAIR principles (Findable, Accessible, Interoperable, and Reusable) and is integrated with other emerging natural product databases, including the Minimum Information About a Biosynthetic Gene Cluster (MIBiG) repository, and the Global Natural Products Social Molecular Networking (GNPS) platform. It is designed as a community-supported resource to provide a central repository for known natural product structures from microorganisms and is the first comprehensive, open access resource of this type. It is expected that the Natural Products Atlas will enable the development of new natural products discovery modalities and accelerate the process of structural characterization for complex natural products libraries.
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http://dx.doi.org/10.1021/acscentsci.9b00806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891855PMC
November 2019

Awakening ancient polar : diversity, evolution and specialized metabolite potential.

Microbiology (Reading) 2019 11;165(11):1169-1180

University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Science, Glasgow, UK.

Polar and subpolar ecosystems are highly vulnerable to global climate change with consequences for biodiversity and community composition. Bacteria are directly impacted by future environmental change and it is therefore essential to have a better understanding of microbial communities in fluctuating ecosystems. Exploration of Polar environments, specifically sediments, represents an exciting opportunity to uncover bacterial and chemical diversity and link this to ecosystem and evolutionary parameters. In terms of specialized metabolite production, the bacterial order , within the phylum are unsurpassed, producing 10 000 specialized metabolites accounting for over 45 % of all bioactive microbial metabolites. A selective isolation approach focused on spore-forming of 12 sediment cores from the Antarctic and sub-Arctic generated a culture collection of 50 strains. This consisted of 39 strains belonging to rare genera including and . This study used a combination of nanopore sequencing and molecular networking to explore the community composition, culturable bacterial diversity, evolutionary relatedness and specialized metabolite potential of these strains. Metagenomic analyses using MinION sequencing was able to detect the phylum across polar sediment cores at an average of 13 % of the total bacterial reads. The resulting molecular network consisted of 1652 parent ions and the lack of known metabolite identification supports the argument that Polar bacteria are likely to produce previously unreported chemistry.
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http://dx.doi.org/10.1099/mic.0.000845DOI Listing
November 2019

Linking biosynthetic and chemical space to accelerate microbial secondary metabolite discovery.

FEMS Microbiol Lett 2019 07;366(13)

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. G4 0RE.

Secondary metabolites can be viewed as a chemical language, facilitating communication between microorganisms. From an ecological point of view, this metabolite exchange is in constant flux due to evolutionary and environmental pressures. From a biomedical perspective, the chemistry is unsurpassed for its antibiotic properties. Genome sequencing of microorganisms has revealed a large reservoir of Biosynthetic Gene Clusters (BGCs); however, linking these to the secondary metabolites they encode is currently a major bottleneck to chemical discovery. This linking of genes to metabolites with experimental validation will aid the elicitation of silent or cryptic (not expressed under normal laboratory conditions) BGCs. As a result, this will accelerate chemical dereplication, our understanding of gene transcription and provide a comprehensive resource for synthetic biology. This will ultimately provide an improved understanding of both the biosynthetic and chemical space. In recent years, integrating these complex metabolomic and genomic data sets has been achieved using a spectrum of manual and automated approaches. In this review, we cover examples of these approaches, while addressing current challenges and future directions in linking these data sets.
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http://dx.doi.org/10.1093/femsle/fnz142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697067PMC
July 2019

Temperature Driven Changes in Benthic Bacterial Diversity Influences Biogeochemical Cycling in Coastal Sediments.

Front Microbiol 2018 22;9:1730. Epub 2018 Aug 22.

The Scottish Association for Marine Science, Scottish Marine Institute, Oban, United Kingdom.

Marine sediments are important sites for global biogeochemical cycling, mediated by macrofauna and microalgae. However, it is the microorganisms that drive these key processes. There is strong evidence that coastal benthic habitats will be affected by changing environmental variables (rising temperature, elevated CO), and research has generally focused on the impact on macrofaunal biodiversity and ecosystem services. Despite their importance, there is less understanding of how microbial community assemblages will respond to environmental changes. In this study, a manipulative mesocosm experiment was employed, using next-generation sequencing to assess changes in microbial communities under future environmental change scenarios. Illumina sequencing generated over 11 million 16S rRNA gene sequences (using a primer set biased toward bacteria) and revealed Bacteroidetes and Proteobacteria dominated the total bacterial community of sediment samples. In this study, the sequencing coverage and depth revealed clear changes in species abundance within some phyla. Bacterial community composition was correlated with simulated environmental conditions, and species level community composition was significantly influenced by the mean temperature of the environmental regime ( = 0.002), but not by variation in CO or diurnal temperature variation. Species level changes with increasing mean temperature corresponded with changes in NH concentration, suggesting there is no functional redundancy in microbial communities for nitrogen cycling. Marine coastal biogeochemical cycling under future environmental conditions is likely to be driven by changes in nutrient availability as a direct result of microbial activity.
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http://dx.doi.org/10.3389/fmicb.2018.01730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115492PMC
August 2018

An Integrative Approach to Decipher the Chemical Antagonism between the Competing Endophytes Paraconiothyrium variabile and Bacillus subtilis.

J Nat Prod 2017 11 15;80(11):2863-2873. Epub 2017 Nov 15.

Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245), Sorbonne Université, Muséum National d'Histoire Naturelle, CNRS , CP 54, 57 rue Cuvier, 75005 Paris, France.

An integrative approach combining traditional natural products chemistry, molecular networking, and mass spectrometry imaging has been undertaken to decipher the molecular dialogue between the fungus Paraconiothyrium variabile and the bacterium Bacillus subtilis, which were isolated as endophytes from the conifer Cephalotaxus harringtonia and are characterized by a strong and mutual antibiosis. From this study, we highlight that bacterial surfactins and a fungal tetronic acid are involved in such competition and that the fungus is able to hydrolyze surfactins to fight against the bacterial partner.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01185DOI Listing
November 2017

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking.

Nat Biotechnol 2016 08;34(8):828-837

Produits naturels - Synthèses - Chimie Médicinale, University of Rennes 1, Rennes Cedex, France.

The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.
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http://dx.doi.org/10.1038/nbt.3597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321674PMC
August 2016

Using Molecular Networking for Microbial Secondary Metabolite Bioprospecting.

Metabolites 2016 Jan 8;6(1). Epub 2016 Jan 8.

Scottish Association for Marine Science, Scottish Marine Institute, Oban PA37 1QA, UK.

The oceans represent an understudied resource for the isolation of bacteria with the potential to produce novel secondary metabolites. In particular, actinomyces are well known to produce chemically diverse metabolites with a wide range of biological activities. This study characterised spore-forming bacteria from both Scottish and Antarctic sediments to assess the influence of isolation location on secondary metabolite production. Due to the selective isolation method used, all 85 isolates belonged to the phyla Firmicutes and Actinobacteria, with the majority of isolates belonging to the genera Bacillus and Streptomyces. Based on morphology, thirty-eight isolates were chosen for chemical investigation. Molecular networking based on chemical profiles (HR-MS/MS) of fermentation extracts was used to compare complex metabolite extracts. The results revealed 40% and 42% of parent ions were produced by Antarctic and Scottish isolated bacteria, respectively, and only 8% of networked metabolites were shared between these locations, implying a high degree of biogeographic influence upon secondary metabolite production. The resulting molecular network contained over 3500 parent ions with a mass range of m/z 149-2558 illustrating the wealth of metabolites produced. Furthermore, seven fermentation extracts showed bioactivity against epithelial colon adenocarcinoma cells, demonstrating the potential for the discovery of novel bioactive compounds from these understudied locations.
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http://dx.doi.org/10.3390/metabo6010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812331PMC
January 2016

Competitive strategies differentiate closely related species of marine actinobacteria.

ISME J 2016 Feb 4;10(2):478-90. Epub 2015 Aug 4.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.

Although competition, niche partitioning, and spatial isolation have been used to describe the ecology and evolution of macro-organisms, it is less clear to what extent these principles account for the extraordinary levels of bacterial diversity observed in nature. Ecological interactions among bacteria are particularly challenging to address due to methodological limitations and uncertainties over how to recognize fundamental units of diversity and link them to the functional traits and evolutionary processes that led to their divergence. Here we show that two closely related marine actinomycete species can be differentiated based on competitive strategies. Using a direct challenge assay to investigate inhibitory interactions with members of the bacterial community, we observed a temporal difference in the onset of inhibition. The majority of inhibitory activity exhibited by Salinispora arenicola occurred early in its growth cycle and was linked to antibiotic production. In contrast, most inhibition by Salinispora tropica occurred later in the growth cycle and was more commonly linked to nutrient depletion or other sources. Comparative genomics support these differences, with S. arenicola containing nearly twice the number of secondary metabolite biosynthetic gene clusters as S. tropica, indicating a greater potential for secondary metabolite production. In contrast, S. tropica is enriched in gene clusters associated with the acquisition of growth-limiting nutrients such as iron. Coupled with differences in growth rates, the results reveal that S. arenicola uses interference competition at the expense of growth, whereas S. tropica preferentially employs a strategy of exploitation competition. The results support the ecological divergence of two co-occurring and closely related species of marine bacteria by providing evidence they have evolved fundamentally different strategies to compete in marine sediments.
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http://dx.doi.org/10.1038/ismej.2015.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737938PMC
February 2016

Molecular networking and pattern-based genome mining improves discovery of biosynthetic gene clusters and their products from Salinispora species.

Chem Biol 2015 Apr 9;22(4):460-471. Epub 2015 Apr 9.

Center for Marine Biotechnology & Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093, USA. Electronic address:

Genome sequencing has revealed that bacteria contain many more biosynthetic gene clusters than predicted based on the number of secondary metabolites discovered to date. While this biosynthetic reservoir has fostered interest in new tools for natural product discovery, there remains a gap between gene cluster detection and compound discovery. Here we apply molecular networking and the new concept of pattern-based genome mining to 35 Salinispora strains, including 30 for which draft genome sequences were either available or obtained for this study. The results provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated the identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation. These efforts revealed considerable metabolite diversity and led to several molecular family-gene cluster pairings, of which the quinomycin-type depsipeptide retimycin A was characterized and linked to gene cluster NRPS40 using pattern-based bioinformatic approaches.
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http://dx.doi.org/10.1016/j.chembiol.2015.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409930PMC
April 2015