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Merging chemical ecology with bacterial genome mining for secondary metabolite discovery

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Journal of Industrial Microbiology & Biotechnology

Abstract

The integration of chemical ecology and bacterial genome mining can enhance the discovery of structurally diverse natural products in functional contexts. By examining bacterial secondary metabolism in the framework of its ecological niche, insights into the upregulation of orphan biosynthetic pathways and the enhancement of the enzyme substrate supply can be obtained, leading to the discovery of new secondary metabolic pathways that would otherwise be silent or undetected under typical laboratory cultivation conditions. Access to these new natural products (i.e., the chemotypes) facilitates experimental genotype-to-phenotype linkages. Here, we describe certain functional natural products produced by Xenorhabdus and Photorhabdus bacteria with experimentally linked biosynthetic gene clusters as illustrative examples of the synergy between chemical ecology and bacterial genome mining in connecting genotypes to phenotypes through chemotype characterization. These Gammaproteobacteria share a mutualistic relationship with nematodes and a pathogenic relationship with insects and, in select cases, humans. The natural products encoded by these bacteria distinguish their interactions with their animal hosts and other microorganisms in their multipartite symbiotic lifestyles. Though both genera have similar lifestyles, their genetic, chemical, and physiological attributes are distinct. Both undergo phenotypic variation and produce a profuse number of bioactive secondary metabolites. We provide further detail in the context of regulation, production, processing, and function for these genetically encoded small molecules with respect to their roles in mutualism and pathogenicity. These collective insights more widely promote the discovery of atypical orphan biosynthetic pathways encoding novel small molecules in symbiotic systems, which could open up new avenues for investigating and exploiting microbial chemical signaling in host–bacteria interactions.

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Acknowledgments

Our work on the discovery of bacterial natural product pathways in functional contexts is supported by the National Institutes of Health (R00-GM097096 and 1DP2CA186575), the Searle Scholars Program (13-SSP-210), and the Damon Runyon Cancer Research Foundation (DFS:05-12). We thank Todd Ciche (Monsanto Company) for a preliminary version of Fig. 1.

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Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, CT, 06520, USA

    Maria I. Vizcaino, Xun Guo & Jason M. Crawford

  2. Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT, 06510, USA

    Jason M. Crawford

  3. Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA

    Maria I. Vizcaino, Xun Guo & Jason M. Crawford

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  1. Maria I. Vizcaino
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  2. Xun Guo
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  3. Jason M. Crawford
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Correspondence to Jason M. Crawford.

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This manuscript is dedicated to Sir David Hopwood on the occasion of his 80th birthday.

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Vizcaino, M.I., Guo, X. & Crawford, J.M. Merging chemical ecology with bacterial genome mining for secondary metabolite discovery. J Ind Microbiol Biotechnol 41, 285–299 (2014). https://doi.org/10.1007/s10295-013-1356-5

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