Merging chemical ecology with bacterial genome mining for secondary metabolite discovery

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.

Figure 1

Phenotypic variation in Photorhabdus. Promoter inversion toggles the bacterium between a pathogenic P-form and an M-form that initiates nematode mutualism. A new understanding of the genetic form switching mechanism enables engineered locked states to examine the metabolic status associated with phenotypic variation. Adapted from Somvanshi et al [62].

Figure 2

Selected natural products from Xenorhabdus and Photorhabdus.

Figure 3

Proposed stilbene and cyclohexanedione biosynthesis. Based on enzyme homology, it is plausible that stilbene biosynthesis could rather proceed as shown for cyclohexanedione biosynthesis.

Figure 4

Proteolytic processing in xenocoumacin biosynthesis and activation. OM, outer membrane; IM, inner membrane.