Development of a Streptomyces venezuelae-Based Combinatorial Biosynthetic System for the Production of Glycosylated Derivatives of Doxorubicin and Its Biosynthetic Intermediates

Abstract: Discovery of novel bioactive natural products from Actinomycetota has decreased, motivating the exploration of rare ecosystems. In this work, we integrated genomics and untargeted metabolomics to profile the biosynthetic capacity of Streptomyces and Nocardia strains isolated from two contrasting, Ramsar-listed Mexican biomes with well-defined ecological features: Cuatro Ciénegas, a semi-arid, oligotrophic karst basin with high microbial endemism, and Calakmul, a tropical rainforest characterized by high biodiversity, seasonal wetlands and limestone-derived alkaline soils. We hypothesized that bacteria isolated from contrasting environments would encode for novel and distinctive subsets of secondary metabolites. Using different metabolo-genomic approaches, a diverse collection of Streptomyces and Nocardia strains was identified, including several potentially novel species. Genome mining revealed a large repertoire of biosynthetic gene clusters (BGCs), many without matches to known metabolites, while molecular networking and dereplication (GNPS, SNAP-MS) exposed extensive chemical diversity within the isolates. Targeted synteny/ortholog analyses (CORASON) linked subsets of metabolites to BGCs, confirming actinomycin and collismycin and identifying komodoquinone-, nocardiopsistin- and rubiginone-like clusters. Notably, bioactivity assays of crude extracts demonstrated effective antifungal effects against Candida albicans SC5314 biofilms and planktonic growth, suggesting their potential therapeutic use. These findings reveal a significant untapped chemical space encoded by Actinomycetota from Ramsar sites, while reinforcing the need for improved tools to connect genomic and metabolomic data for natural product discovery.

TL;DR: In this paper, a cell-free coupled transcription-translation (TX-TL) system was proposed to examine natural product biosynthetic pathways in a test tube, where the key advantages of this approach are the reduced experimental time scales and controlled reaction conditions.

TL;DR: In this paper, a reconstituted version of the enzyme in the daunorubicin/doxorubicain pathway was shown to be active in an in vitro system.

TL;DR: This minireview summarizes the genome-based genome mining (GM) of diverse BCGs and genome exploration (GE) of versatile biocatalytic enzymes, and other enzymes involved in maintenance and regulation of metabolism of S. peucetius.

TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.

TL;DR: It is shown that several of these vectors can be introduced into Streptomyces fradiae, a strain that is notoriously difficult to transform by PEG-mediated protoplast transformation.

TL;DR: The plant epimerase undergoes a complex regulation and could control the carbon flux into the vitamin C pathway in response to the redox state of the cell, stress conditions, and GDP-sugar demand for the cell wall/glycoprotein biosynthesis.

TL;DR: In a survey of microbial systems capable of generating unusual metabolite structural variability, Strepto myces venezuelae ATCC 15439 is notable in its ability to produce two distinct groups of macrolide antibiotics as discussed by the authors.