Mining and unearthing hidden biosynthetic potential

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Abstract

Genetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.

Abstract

Natural products are an important source of bioactive compounds and have versatile applications in different fields, but their discovery is challenging. Here, the authors review the recent developments in genome mining for discovery of natural products, focusing on compounds from unconventional microorganisms and microbiomes.

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Most cited references 136

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Natural Products as Sources of New Drugs from 1981 to 2014.

David J Newman, Gordon M. Cragg (2016)

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small molecules approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.

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Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters.

Peter Cimermancic, Marnix H Medema, Jan Claesen … (2014)

Although biosynthetic gene clusters (BGCs) have been discovered for hundreds of bacterial metabolites, our knowledge of their diversity remains limited. Here, we used a novel algorithm to systematically identify BGCs in the extensive extant microbial sequencing data. Network analysis of the predicted BGCs revealed large gene cluster families, the vast majority uncharacterized. We experimentally characterized the most prominent family, consisting of two subfamilies of hundreds of BGCs distributed throughout the Proteobacteria; their products are aryl polyenes, lipids with an aryl head group conjugated to a polyene tail. We identified a distant relationship to a third subfamily of aryl polyene BGCs, and together the three subfamilies represent the largest known family of biosynthetic gene clusters, with more than 1,000 members. Although these clusters are widely divergent in sequence, their small molecule products are remarkably conserved, indicating for the first time the important roles these compounds play in Gram-negative cell biology. Copyright © 2014 Elsevier Inc. All rights reserved.

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Regulation of fungal secondary metabolism.

Axel A. Brakhage (2013)

Fungi produce a multitude of low-molecular-mass compounds known as secondary metabolites, which have roles in a range of cellular processes such as transcription, development and intercellular communication. In addition, many of these compounds now have important applications, for instance, as antibiotics or immunosuppressants. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of the fungal secondary metabolite biosynthesis gene clusters are silent under standard cultivation conditions. In this Review, I describe our current understanding of the regulatory elements that modulate the transcription of genes involved in secondary metabolism. I also discuss how an improved knowledge of these regulatory elements will ultimately lead to a better understanding of the physiological and ecological functions of these important compounds and will pave the way for a novel avenue to drug discovery through targeted activation of silent gene clusters.

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Author and article information

Contributors

Christian Hertweck:

ORCID: http://orcid.org/0000-0002-0367-337X

christian.hertweck@leibniz-hki.de

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 23 June 2021

Publication date PMC-release: 23 June 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 3864

Affiliations

[1 ]GRID grid.418398.f, ISNI 0000 0001 0143 807X, Department of Biomolecular Chemistry, , Leibniz Institute for Natural Product Research and Infection Biology, HKI, ; Jena, Germany

[2 ]GRID grid.9613.d, ISNI 0000 0001 1939 2794, Faculty of Biological Sciences, , Friedrich Schiller University Jena, ; Jena, Germany

Author information

Christian Hertweck http://orcid.org/0000-0002-0367-337X

Article

Publisher ID: 24133

DOI: 10.1038/s41467-021-24133-5

PMC ID: 8222398

PubMed ID: 34162873

SO-VID: 76524a95-c12c-4c9d-af28-25f46907510e

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 18 December 2020

Date accepted : 4 June 2021

Funding

Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);

Award ID: SFB 1127

Award ID: Microverse

Award ID: Leibniz Award

Award Recipient : Christian Hertweck

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ScienceOpen disciplines: Uncategorized

Keywords: computational biology and bioinformatics,biosynthesis,natural products,drug discovery and development

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ScienceOpen disciplines: Uncategorized

Keywords: computational biology and bioinformatics, biosynthesis, natural products, drug discovery and development

Mining and unearthing hidden biosynthetic potential

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Algerian Journal of Natural Products

Most cited references 136

Natural Products as Sources of New Drugs from 1981 to 2014.

Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters.

Regulation of fungal secondary metabolism.

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