Automated Identification of Depsipeptide Natural Products by an Informatic Search Algorithm

Abstract

Nonribosomal depsipeptides are a class of potent microbial natural products, which include several clinically approved pharmaceutical agents. Genome sequencing has revealed a large number of uninvestigated natural-product biosynthetic gene clusters. However, while novel informatic search methods to access these gene clusters have been developed to identify peptide natural products, depsipeptide detection has proven challenging. Herein, we present an improved version of our informatic search algorithm for natural products (iSNAP), which facilitates the detection of known and genetically predicted depsipeptides in complex microbial culture extracts. We validated this technology by identifying several depsipeptides from novel producers, and located a large number of novel depsipeptide gene clusters for future study. This approach highlights the value of chemoinformatic search methods for the discovery of genetically encoded metabolites by targeting specific areas of chemical space.

The evolution of genome mining in microbes – a review

“…96,99 This is further supported by the availability of cheminformatic approaches like MS/MS networking 29,100 or iSNAP 101 that allow the automatic mapping of identied and in silico analyzed NRP (and RiPP) BGCs to mass spectrometric data. 73,[101][102][103][104] Genome mining, for example, led to the identication of NRP secondary metabolites also from organisms, such as Staphylococcus aureus, 105 which usually are not regarded as prolic secondary metabolite producers. In the case of the biosynthesis of the siderophore coelichelin from the model actinomycete Streptomyces coelicolor M145, genome mining revealed new biochemical insights about NRPS biochemistry.…”

Draft Genome Sequence of Streptomyces silvensis ATCC 53525, a Producer of Novel Hormone Antagonists

“…Among these, we identified a putative nonribosomal peptide gene cluster responsible for the production of the oxytocin antagonist cyclic peptides. We also found gene clusters responsible for the production of faeriefungin and echinomycin ( 5 ), which we had previously identified as natural products produced by S. silvensis . In addition to these established products of S. silvensis , we also observed gene clusters with high homology to those for production of the known molecules prodigiosin, coelichelin, and griseobactin.…”

An automated Genomes-to-Natural Products platform (GNP) for the discovery of modular natural products

“… 26 . GNP includes several new cleavage options, including ester cleavage for depsipeptides and inverse ester and thioether cleavages for abnormal MS/MS cleavage patterns 65 . GNP also has the ability to generate images of each matched fragment or structure to facilitate matched fragment verification.…”