The present work queried metagenomes of several sponge species by making use of a minimal set of core enzymes that postulate to be necessary to produce small peptidic NPs, revealing a variety of novel BGC architectures, many of which showed conservation among sponge host phylogenies and were encoded in the genomes of diverse sponge-associated bacteria.
Abstract
Marine sponges are known sources of bioactive natural products (NPs), many of which are produced by associated bacterial symbionts via encoded biosynthetic gene clusters (BGCs). A particularly interesting subclass of sponge-derived NPs is comprised of small, brominated alkaloids, which are recovered from diverse habitats and host sponge taxonomies. Despite having been described decades ago, most of these NPs do not have an elucidated biosynthetic origin. We queried metagenomes of several sponge species by making use of a minimal set of core enzymes that we postulate to be necessary to produce these small peptidic NPs: an FADH2-dependent halogenase and an AMP-binding adenylation enzyme. This revealed a variety of novel BGC architectures, many of which showed conservation among sponge host phylogenies and were encoded in the genomes of diverse sponge-associated bacteria. Furthermore, we identified a BGC in the sponge G. barretti that is potentially linked to the production of the iconic barettins, given its enzymatic machinery and specific acidobacterial origin. The present work contributes to the challenging quest to link orphan brominated NPs to their parent BGCs in the sponge holobiont and beyond.
An integrative perspective on Microbispora as an underexplored but promising source of structurally diverse and bioactive natural products for drug discovery is provided.
Microbial natural products are the source of over 70% of all known antibiotics, yet the pace of their discovery has slowed significantly since its peak in the mid-20th century. This stagnation is largely due to the repeated isolation of known compounds from readily culturable microorganisms, while the vast majority of microbial biosynthetic gene clusters (BGCs) remain silent and unexpressed under typical laboratory conditions. The convergence of genomics, synthetic biology, and high resolution analytical chemistry now provides a powerful toolkit to unlock this cryptic biosynthetic potential. This thesis presents a strategy that integrates these disciplines to awaken silent BGCs and discover novel bioactive molecules.
A genome mining approach was utilised to identify 22 promising BGCs from diverse actinobacteria, prioritised for their predicted novelty. To activate their expression, a suite of synthetic biology and molecular cloning strategies was implemented in both native and engineered heterologous hosts. This systematic activation campaign yielded several significant outcomes: (i) the linking of three known compounds to their previously unknown BGCs; and (ii) the discovery and structural elucidation of two novel natural products. Notably, one of the compounds represents a new class of calcium-dependent antibiotics with potent antimicrobial activity.
In conclusion, this research demonstrates the efficacy of a genome-led approach to drug discovery. It has successfully translated genomic data into tangible chemical matter, functionally characterised previously cryptic BGCs, and contributed a novel class of antibiotics to the global pipeline for combating infectious diseases.
Marine-derived rare actinomycetes are a chemically prolific yet underexploited source of structurally diverse secondary metabolites. In this review, rare actinomycetes are operationally defined as marine-derived non-Streptomyces actinomycetes that remain comparatively underexplored yet possess demonstrated or predicted capacity for specialized-metabolite biosynthesis. Genome sequencing has revealed that their biosynthetic potential greatly exceeds the range of metabolites recovered under standard cultivation conditions. However, many reported compounds remain only loosely associated with the gene clusters that encode them. This review provides a biosynthesis-centered perspective on marine-derived rare actinomycetes, focusing on secondary metabolites for which biosynthetic gene clusters (BGCs) or pathways have been proposed, experimentally assessed, or functionally validated. It focuses on compounds reported after 2017, along with earlier metabolites whose biosynthetic origins were resolved only later. Representative examples are organized by genus and structural class and weighed according to the level of evidence linking each metabolite to its BGC, ranging from bioinformatic prediction and metabolomic correlation to validation by gene inactivation, heterologous expression, and enzymatic characterization. The surveyed metabolites include polyketides, nonribosomal peptides, polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrids, siderophores, angucyclines, anthracyclines, macrolides, diketopiperazine derivatives, and other unusual scaffolds. Collectively, these findings indicate how integrating genome mining, metabolomics, and molecular networking with targeted biosynthetic experiments can accelerate marine natural product discovery and unravel novel enzymatic functions and biosynthetic mechanisms in rare actinomycetes.
Ju-Wan Son, Hyeonju Park, Sang-He-On Jung et al.· Marine Drugs· 0 citations
The integrated bioinformatics pipeline enabled the reconstruction of 37 medium-to-high-quality metagenome-assembled genomes (MAGs), and recovered 147 BGCs mostly from Pseudomonadota, Actinomycetota, and Acidobacteriota phyla, highlighting the Siwa Oasis as a promising reservoir of unexplored biosynthetic potential and a valuable resource for natural product discovery to address global health challenges.
Muhammad A. Ajagbe, Shimaa F Ahmed, Amged A. Ouf et al.· World Journal of Microbiolog...· 0 citations
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