Elucidating the Rimosamide-Detoxin Natural Product Families and Their Biosynthesis Using Metabolite/Gene Cluster Correlations

Abstract

As microbial genome sequencing becomes more widespread, the capacity of microorganisms to produce an immense number of metabolites has come into better view. Utilizing a metabolite/gene cluster correlation platform, the biosynthetic origins of a new family of natural products, the rimosamides, were discovered. The rimosamides were identified in Streptomyces rimosus and associated with their NRPS/PKS-type gene cluster based upon their high frequency of co-occurrence across 179 strains of actinobacteria. This also led to the discovery of the related detoxin gene cluster. The core of each of these families of natural products contains a depsipeptide bond at the point of bifurcation in their unusual branched structures, the origins of which are definitively assigned to nonlinear biosynthetic pathways via heterologous expression in Streptomyces lividans. The rimosamides were found to antagonize the antibiotic activity of blasticidin S against Bacillus cereus.

A computational framework for systematic exploration of biosynthetic diversity from large-scale genomic data

“…To showcase the power of our workflow for the analysis of large BGC collections and highresolution mapping of GCF biosynthetic diversity, we focused on the detoxin and rimosamide GCFs 38 . Our comprehensive analysis of the selected actinobacterial genomes revealed these BGCs to be taxonomically widespread and architecturally diverse (Fig.…”

“…The rimosamide BGC differs from those of the detoxins by having an additional NRPS, which encodes for further elaboration of the common detoxin/rimosamide core scaffold with isobutyrate and glycine 38 . Aside from the more common NRPS and PKS genes, the fact that the tauD gene was present across all members of this family caught our attention.…”

“…Interestingly, this family also includes enzymes across fungi, bacteria and plants that catalyze hydroxylations, desaturations, ring expansions, and ring formations, among other transformations. To date, the role of tauD in detoxin and rimosamide biosynthesis is unknown, but it has been suggested to be responsible for the proline oxidation observed in some analogs 38 .…”

Omics-based natural product discovery and the lexicon of genome mining

“…While there is clear precedent for the use of both terms to describe BGCs that have yet to be linked to the small molecules they encode, we have followed the original suggestion by Gross for the use of orphan[25]. Complicating the matter is the alternative use of the term orphan to describe compounds whose cognate BGC has not been identified[26]. This later usage appears fitting given the more colloquial interpretation of orphan as a lack of parents or affiliation.…”

“…Comparing BGC distributions with metabolomic profiles has been termed “pattern-based genome mining” and used to compare large numbers of closely related bacteria[48,49]. Similar approaches were used to identify the rimosamide, detoxin, and tambromycin NPs and their associated BGCs[26,50], with the later approach termed metabologenomics. Genomics and metabolomics have also been coupled to discover new NPs from cyanobacteria[51].…”