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. 2016 Dec 16;11(12):3452-3460.
doi: 10.1021/acschembio.6b00779. Epub 2016 Nov 15.

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

Ryan A McClure  1 , Anthony W Goering  1 , Kou-San Ju  2 , Joshua A Baccile  3 , Frank C Schroeder  3 , William W Metcalf  2   4 , Regan J Thomson  1 , Neil L Kelleher  1
Affiliations

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

Ryan A McClure et al. ACS Chem Biol. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Representative structures of the rimosamides and the detoxins. Key differences between the rimosamides and detoxins are highlighted above and include the addition of a glycine residue (red), incorporation of an isoleucine residue (blue), and incorporation of an iso-butyrate (green).
Figure 2
Figure 2
Biosynthesis of the rimosamides. (A) The rimosamide biosynthetic gene cluster. Genes depicted as red arrows are NRPS. The purple arrow is NRPS/PKS hybrid. The green arrow is taurine dioxygenase. Blue arrows are various, and gray arrows are hypothetical ORFs. (B) NRPS and PKS domain predictions are shown for RmoG, RmoH, and RmoI. Functional annotations of additional ORFs in NPRS_502 can be found in Table S2. (C) Heterologous expression of the rimosamides in S. lividans 66.
Figure 3
Figure 3
Proposed biosynthetic pathway for the production of rimosamide C from NRPS_502. Production of the rimosamides breaks the normal rules of colinearity in assembly line biosynthesis and is proposed to culminate in formation of an unusual depsipeptide bond formation to generate branching peptide chains. A taurine dioxygenase (RmoL) is likely responsible for the oxidation of the C-3 position of the modified proline core.
Figure 4
Figure 4
Analysis of the rimosamide and detoxin BGCs. (A) The rimosamide (top) and detoxin (bottom) BGCs share many of the same ORFs. Homologous ORFs are highlighted, and percentage sequence identity is shown. (B) NRPS and PKS domain predictions are shown for DetF and DetG. (C) Domains responsible for the incorporation of specific monomers as highlighted in the rimosamides (top) and detoxins (bottom).
Figure 5
Figure 5
Disk diffusion assay of rimosamide A (RA) as an antagonist of the antibiotic blasticidin S (BS) against B. cereus. The assay plate is shown on the top and tabulated results on the bottom. With decreasing concentrations of the rimosamide A, the antagonism of blasticidin S decreases (i.e., inhibition zone increases).
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