Mass spectrometry as the unifying force in natural product sciences

Mehdi A. Beniddir

Mehdi Beniddir is a Full Professor of natural products chemistry at the Faculty of Pharmacy of Paris-Saclay University. He graduated in pharmacy and received his MSc degree from Paris-Sud University in 2009. He obtained his PhD at the Institut de Chimie des Substances Naturelles (ICSN-CNRS) in 2012. He was subsequently a postdoctoral fellow at Paris-Saclay University. His research interests include the streamlined discovery of intricate natural substances from plants, marine invertebrates, and micro-organisms using prioritization strategies integrating the principles of decision theory to mimic the chemist's intuition in targeting natural substances.

Nadja B. Cech

Dr Nadja Cech is Patricia A. Sullivan Professor of Chemistry at the University of North Carolina at Greensboro (UNCG). There, she leads a dynamic research group working to develop metabolomics tools to study natural products. The Cech Group has pioneered new methods for the integration of chemical and biological datasets to predict active molecules and synergists from complex mixtures.

Roger Linington

Roger Linington is a Professor of Chemistry and Tier 1 Canada Research Chair in Natural Products and High-Throughput Screening at Simon Fraser University in Canada. His research program focuses on the development of tools and technologies for the discovery of bioactive natural products. His interests include mass spectrometry-based metabolomics, high-throughput screen design and development, and data integration strategies for omics-based studies. His group leads the development of the Natural Products Atlas database of microbial natural products.

Neha Garg

Neha Garg is a Blanchard Professor in the School of Chemistry and Biochemistry at Georgia Institute of Technology, USA. Dr Garg's group applies interdisciplinary approaches in microbiology, (bio)chemistry, microscopy, mass spectrometry, and -omics to unveil the role of microbial, host, and chemical environments in the production of small molecule natural products and to decipher functionally relevant small molecules that mediate microbe–drug, microbe–microbe, and microbe–host interactions. She hopes her research will generate a fundamental understanding of how beneficial bacteria prevent pathogen colonization and proliferation during infection and translate this understanding into the development of new drug targets and alternative therapies.

The molecular characterization of our natural world with mass spectrometry is at a pivotal and exciting stage. We are witnessing a fundamental transformation in how we approach natural product analysis in a way that parallels the genomic revolution of the past two decades. The catalyst for this transformation is not merely instrumental advancement, but rather the expanding recognition that mass spectrometry serves as a universal analytical language capable of interrogating natural products across every scale of biological organization.

This evolution has been driven by converging developments stemming from advances in ion sources, high-throughput metabolomics, and integration of data visualization and organization approaches such as molecular networking, microbeMAAST and in silico methods for annotation prediction. As genomic information proliferates exponentially, the scientific community faces an urgent imperative: to understand what functional molecules genes encode, how to search them across datasets, and how specialized metabolites orchestrate biological processes from intracellular signaling to ecosystem-level dynamics. This themed issue highlights recent advancements in natural product mass spectrometry that are enabling these goals while highlighting fresh challenges and future horizons for natural product research.

Modern mass spectrometry has expanded our access to the natural product chemical universe. Parsley et al.¹ illuminate the vast “dark space” of bioactive peptides whose functional potential remains largely undiscovered. Natural product peptides embody inherent bioactivities serving as templates inspiring new chemistries and molecular scaffolds in drug discovery and agrotechnology. Yet mapping this diverse peptidome is obfuscated by diverse and multiple molecular transformations in non-ribosomal sequences and post-translational modifications in ribosomal products as well as difficult-to-predict cyclization reactions in peptides.

Contemporary mass spectrometry achieves unprecedented resolving power, rapid gas-phase separations via ion mobility, and versatile multistage fragmentation techniques that characterize traditionally difficult-to-sequence peptide modifications via enhanced gas-phase technologies. This information can be integrated with complementary ‘Omics’ approaches to predict peptide structure through transcripts, motifs, biosynthetic pathways, and the machinery involved in peptide biogenesis. This expanded access extends across multiple natural product domains through accelerated discovery workflows. Shepherd et al.² demonstrate how mass spectrometry has revolutionized enzyme engineering through label-free screening suitable for diverse biochemical systems. Over the past decade, advancements in mass spectrometry, separation science, and hyphenated methods have enabled streamlined analysis of large sample volumes while maximizing data richness and dimensionality. These developments have transformed enzyme discovery through directed evolution screening, enabling rapid assessment of functional variants within large combinatorial libraries. Covington et al.³ address how traditional bioactivity-guided microbial natural product discovery accessed only a small fraction of total natural product potential, with genomic evidence suggesting the products of the vast majority of biosynthetic pathways remain unidentified. High-throughput mass spectrometry and comparative metabolomics now facilitate comprehensive discovery, promising to unlock the reservoir of microbial natural products previously concealed by one-molecule-at-a-time approaches. Together, these advances represent an acceleration paradigm that increasingly underlies natural product discovery across kingdoms.

Characterizing the chemical complexity of natural environments demands integrated analytical strategies. Marine ecosystems present extraordinary complexity, a point highlighted by Mauduit et al.,⁴ who describe marine exometabolites (small molecules released by marine organisms into seawater) that collectively contribute to the chemical seascape. Different sampling methods coupled with MS-based metabolomic analyses enable characterization of benthic seawater chemical composition, offering avenues for describing marine exometabolite structural diversity and deciphering their functions across ecological contexts. Kulkarni et al.⁵ extend this theme to host–microbiome systems, exploring how specialized metabolites mediate universal chemical crosstalk essential for microbial communication, biofilm formation, competition elimination, symbiosis establishment, immune evasion, and stress response. The relatively low abundance of microbial metabolites in complex biological matrices presents major challenges to elucidating small molecule mediators of host–microbe interactions. Recent advances in expansion of use of model systems including mammalian cell coculture and organoids, mass spectrometry instrumentation, experimental methods, and computational approaches coupled with model organisms have enabled fundamental discoveries of small molecule-mediated mechanisms across diverse biological ecosystems. These complementary efforts ranging from open ocean chemistry to intimate host–microbiome dialogues illustrate how mass spectrometry enables systematic chemical interrogation at multiple biological scales.

Contemporary botanical research faces comparable complexity challenges. Kellogg et al.⁶ demonstrate how untargeted mass spectrometry metabolomics profiles complex botanical mixtures, providing detailed datasets capable of taxonomically classifying samples, detecting adulteration, and revealing variation between plant materials and their nutritional, medicinal, or toxicological effects. Mass spectrometry-based metabolomics offers comprehensive approaches to effective identification and characterization, crucial for evaluating safety and efficacy of botanical dietary supplements, nutraceuticals, and herbal medicines. Mikropoulou et al.⁷ reflect on how the therapeutic value of natural products, evident in their ethnopharmacological history and prominence in marketed drugs, has been undermined by labor-intensive isolation and structural challenges alongside patenting, sourcing, and preclinical evaluation issues. Current bioavailability research focuses predominantly on well-known plants or specific compound classes, leaving many candidates underexplored. The interplay between gut microbiota and natural products remains largely overlooked in contemporary drug development. Recent innovations in mass spectrometry, smart library screening, dereplication, and molecular networking have significantly improved the natural product pipeline, though the integration of metabolomics and big data analytics remains underutilized in natural product prioritization and drug development. These intersecting botanical studies underscore how mass spectrometry now enables comprehensive evaluation of plant-derived medicines from chemical characterization through bioavailability prediction and interaction assessment.

From raw metabolomic data to integrated chemical understanding, information processing and visualization represent critical analytical frontiers. van der Hooft and coworkers⁸ provide essential guidance on data visualization strategies in untargeted metabolomics. LC-MS/MS datasets are sizable and abstract, requiring numerous processing steps that depend heavily on expert human interpretation. Effective visualizations facilitate this laborious task, enabling researchers to validate preprocessing steps and interpret complex data components at each analytical stage. Best practices in data visualization, coupled with practical tools and roadmaps, enhance effective and transparent communication of results. Complementing these visualization approaches, Rutz et al.⁹ challenge the traditional molecule-first paradigm that restricts scalability in natural products research. While metabolomics has become routine, the field remains focused on individual molecules or small sets of compounds. By leveraging bioinformatics and chemoinformatics tools to unlock the full potential of natural extract libraries, researchers can embrace broader insights beyond single-compound characterization, advancing scalable exploration of botanical and microbial diversity. Together, visualization and annotation tools are transforming raw mass spectrometric data into coherent chemical knowledge at unprecedented scale.

This themed issue showcases how modern mass spectrometry has become an indispensable analytical backbone revealing hidden and complex dimensions of natural product science. Collectively, these expert reviews demonstrate that mass spectrometry is far more than an analytical tool. Instead, it has become a conceptual framework enabling natural product scientists to organize, understand, and navigate extraordinary chemical diversity. As the field enters the Big Data era, integration of advanced mass spectrometry with chemoinformatics, and systems-level biological understanding, will continue to accelerate discovery and deepen our appreciation for how specialized metabolites impact biological processes at every scale.

Acknowledgements

The authors acknowledge the use of GPT-based language models to assist with polishing the text of this editorial.

References

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