Genomic potential of Streptomyces roseochromogenes NRRL 3504 for the production of specialized metabolites: analysis in silico

Abstract

Streptomyces roseochromogenes NRRL 3504 is the only known producer of aminocoumarin antibiotic clorobiocin – an inhibitor of bacterial DNA-gyrase and topoisomerase IV. Sequencing of NRRL 3504 genome revealed a plethora of specialized metabolite biosynthetic gene clusters (BGCs) within the latter, attesting to the significant potential of this species for the production of various as-yet-unknown bioactive compounds. Here we report bioinformatic analysis of NRRL 3504 genome aimed to better understand what kind of small molecules this strain could produce and genetic mechanisms that may limit their production. In addition to the most commonly applied bioinformatic service for BGCs detection antiSMASH, we turned to alternative tools for secondary metabolome in silico analysis such as PRISM, DeepBGC, ARTS, SEMPI and GECCO. While different genome mining applications pointed to a common core set of BGCs within the NRRL 3504, each tool having its own algorithm of BGCs detection also discovered certain number of non-overlapping clusters. This was especially true for machine learning tool DeepBGC that unearthed the biggest number of BGCs. To summarize the obtained results we used BGCViz tool, which visualizes and integrates BGC annotations from various sources by using genomic coordinates. We discuss the genetic and structural diversity of the BGCs and outline the most interesting, in opinion, targets for further investigations. Most of the described BGCs are most likely silent due to very low or zero transcription. Therefore, it might be needed to find the ways to activate the transcription of the BGCs of interest. To this end, we mined NRRL 3504 genome for the orthologs of global regulatory genes known to be involved in regulation of specialized metabolism of S. coelicolor A3(2). We were able to identify almost all plausible global regulators of interest in NRRL 3504, implying that overall scheme of regulation of specialized metabolism in A3(2) and NRRL 3504 might be similar. Results of our work set the stage for a more detailed experimental scrutiny of silent specialized metabolome of NRRL 3504.