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Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra

Nature Microbiology volume 3, pages 319–327 (2018)Cite this article

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Abstract

Peptidic natural products (PNPs) include many antibiotics and other bioactive compounds. While the recent launch of the Global Natural Products Social (GNPS) molecular networking infrastructure is transforming PNP discovery into a high-throughput technology, PNP identification algorithms are needed to realize the potential of the GNPS project. GNPS relies on the assumption that each connected component of a molecular network (representing related metabolites) illuminates the ‘dark matter of metabolomics’ as long as it contains a known metabolite present in a database. We reveal a surprising diversity of PNPs produced by related bacteria and show that, contrary to the ‘comparative metabolomics’ assumption, two related bacteria are unlikely to produce identical PNPs (even though they are likely to produce similar PNPs). Since this observation undermines the utility of GNPS, we developed a PNP identification tool, VarQuest, that illuminates the connected components in a molecular network even if they do not contain known PNPs and only contain their variants. VarQuest reveals an order of magnitude more PNP variants than all previous PNP discovery efforts and demonstrates that GNPS already contains spectra from 41% of the currently known PNP families. The enormous diversity of PNPs suggests that biosynthetic gene clusters in various microorganisms constantly evolve to generate a unique spectrum of PNP variants that differ from PNPs in other species.

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Fig. 1: Network-based and network-independent strategies for variable PNP identification.
Fig. 2: VarQuest pipeline.
Fig. 3: Peptide network of the cyclosporin family in the PNPdatabase extended by the newly identified cyclosporin variants.

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Acknowledgements

We thank K. Vyatkina for fruitful discussions and A. Prjibelski for help with manuscript preparation. The work of A.G., A.M., A.S., A.K. and P.A.P. was supported by the Russian Science Foundation (grant 14-50-00069). The work of H.M. and P.A.P. was supported by the US National Institutes of Health (grant 2-P41-GM103484).

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Authors and Affiliations

  1. Center for Algorithmic Biotechnology, Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg, Russia

    Alexey Gurevich, Alla Mikheenko, Alexander Shlemov, Anton Korobeynikov & Pavel A. Pevzner

  2. Department of Mathematics and Mechanics, Saint Petersburg State University, Saint Petersburg, Russia

    Anton Korobeynikov

  3. Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA

    Hosein Mohimani & Pavel A. Pevzner

  4. Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA

    Hosein Mohimani

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Contributions

A.G. implemented the VarQuest algorithm. A.S. and A.K. improved and sped up the DEREPLICATOR software. A.G., A.M. and H.M. designed the webserver. A.G. and A.M. did the VarQuest benchmarking. H.M. and P.A.P. designed and directed the work. A.G., H.M. and P.A.P. wrote the manuscript.

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Correspondence to Pavel A. Pevzner.

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Competing interests

P.A.P. has an equity interest in Digital Proteomics—a company that may potentially benefit from the research results. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies

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Gurevich, A., Mikheenko, A., Shlemov, A. et al. Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra. Nat Microbiol 3, 319–327 (2018). https://doi.org/10.1038/s41564-017-0094-2

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