The undiscovered natural product potential of Actinomycetes

Authors: CARABALLO-RODRIGUEZ, ANDRES - University Of California, San Diego; CUMSILLE, ANDRES - Federico Santa María Technical University; MAGYARI, SAROLT - Swiss Federal Institute Of Technology Zurich; TABOADA-ALQUERQUE, MARIA - Technical University Of Cartagena; BEHSAZ, BEHAR - Carnegie Mellon University; LEAO, TIAGO - Vale Technological Institute; Broders, Kirk; EL ABIEAD, YASIN - University Of California, San Diego; CLEMENT, JASON - Baruch S Blumberg Institute; CHARRON-LAMOUREUX, VINCENT - University Of California, San Diego; ZUFFA, SIMONE - University Of California, San Diego; NOTHIAS, LOUIS-FELIX - University Of California, San Diego; HU, MENGZHOU - University Of California, San Diego; LEONE, CHRISTOPHER - University Of California, San Diego; KAKHKHOROV, SARVAR - University Of California, San Diego; CAMARA, BEATRIZ - Federico Santa María Technical University; MOHIMANI, HOSEIN - Carnegie Mellon University; DORRESTEIN, PIETER - University Of California, San Diego

Submitted to: Journal of Antibiotics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/15/2025
Publication Date: 12/2/2025
Citation: Caraballo-Rodriguez, A.M., Cumsille, A., Magyari, S., Taboada-Alquerque, M., Behsaz, B., Leao, T., Broders, K., El Abiead, Y., Clement, J.A., Charron-Lamoureux, V., Zuffa, S., Nothias, L.-F., Hu, M., Leone, C., Kakhkhorov, S.A., Camara, B., Mohimani, H., Dorrestein, P.C. 2025. The undiscovered natural product potential of Actinomycetes. Journal of Antibiotics. https://doi.org/10.1038/s41429-025-00876-x.
DOI: https://doi.org/10.1038/s41429-025-00876-x

Interpretive Summary: The actinomycetes are a group of bacteria that have been foundational for the discovery of new naturally occurring compounds with applications in pharmaceutical development and biotechnology. However, despite decades of research efforts to link specific genes in the bacteria to known metabolites or molecules, most molecules remain uncharacterized. New methods for high throughput identification of metabolites will help bridge the gap between genetic potential and novel molecule production by bacterial strains. An ARS scientist in Peoria, IL, collaborated with a network of scientists from 10 academic institutions led by University of California, San Diego, to expand our understanding of the novel molecule potential of actinomycetes by collecting and analyzing the chemical compounds secreted, known as the metabolome, of 1,066 microbial strains. This resulted in the production of nearly two million metabolite profiles from which 2,352 molecules were detected. These included a number of biologically active molecules used in drug discovery and chemical ecology. More importantly, the metabolite profiles and predicted molecules were deposited in a public database, and can be used by all scientists in efforts to accelerate the discovery of new microbial molecules and improve our understanding of microbial metabolites across a wide range of ecosystems, including plants, soil, insects, animals, and humans. Moreover, novel microbial molecules hold immense potential for various applications, ranging from aquaculture and agriculture to biotechnology and the study of microbial-mediated human health conditions.

Technical Abstract: Actinomycetes have been a cornerstone species for the discovery of bioactive natural products with applications in pharmacotherapy and biotechnology. To expand the experimental evidence of their biosynthetic potential, we collected liquid-chromatography mass spectrometry untargeted metabolomics data on 948 microbial strains, mostly from Actinomycetes. This resulted in nearly two million MS/MS spectra, with an annotation rate of 13.3% corresponding to 2,352 annotated molecules. Despite the efforts to link biosynthetic gene clusters to known molecules, most remain uncharacterized. This highlights the need for metabolomic data to bridge the gap between genomic potential and metabolite production. Although many unannotated spectra might correspond to different ion forms of the same molecule, the large amount of unknown molecules present in these datasets indicate that a significant number of natural products remain to be discovered, even within one of the most thoroughly studied sets of organisms. We provide a large metabolomics dataset as a public resource for data mining of microbial molecules and highlight its value by demonstrating the detection of edapochelins, recently disovered non-ribosomal peptides.