Aug 2026· Fitoterapia· Vol 194, pp.
107441
· 0 citations· 178 references
Medicine
TL;DR
This review emphasizes the unique capacity of Aspergillus species to generate structurally diverse IDKPs and highlights the potential of genome mining and biosynthetic gene cluster (BGC) analysis for uncovering previously unexplored IDKP biosynthetic pathways.
Abstract
Indole diketopiperazine (IDKP) alkaloids are widely recognized as an important class of rigid three-dimensional scaffolds in microbial secondary metabolism and possess a broad spectrum of biological properties with therapeutic potential. For the past over half-century, great achievements had been made in discovery, biosynthetic characterization, and pharmacological investigation of novel IDKPs from the genus Aspergillus. However, despite the increasing number of reported compounds and growing understanding of their biosynthetic pathways, a systematic overview specifically focusing on Aspergillus-derived IDKPs remains lacking. Herein, we provide a comprehensive overview of Aspergillus-derived IDKPs (1-444), integrating their occurrence, structural diversity, biosynthetic logic, and biological activities. Beyond summarizing the reported metabolites, this review emphasizes the unique capacity of Aspergillus species to generate structurally diverse IDKPs and highlights the potential of genome mining and biosynthetic gene cluster (BGC) analysis for uncovering previously unexplored IDKP biosynthetic pathways. Current challenges and future perspectives associated with expanding the chemical diversity and therapeutic potential of Aspergillus-derived IDKPs are also discussed.
An integrative perspective on Microbispora as an underexplored but promising source of structurally diverse and bioactive natural products for drug discovery is provided.
It is proposed that scaffold enrichment in specific evolutionary lineages, when integrated with enzyme family expansion and functional divergence, may provide a complementary framework for prioritizing candidate tailoring enzymes.
Yalan Zhao, Mengyao Li, Shasha Zuo et al.· Molecules· 0 citations
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.
The genus Talaromyces is an important source of structurally diverse secondary metabolites, yet the conservation and diversification of its biosynthetic potential remain incompletely understood at the genus level. Here, we performed comparative genomic and biosynthetic analyses of 24 Talaromyces species to characterize biosynthetic gene cluster (BGC) diversity, gene cluster family (GCF) distribution, and potential relevance to antifungal natural-product discovery. Genome mining identified 1550 BGCs, ranging from 41 to 81 per species, with polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS), terpene, and hybrid PKS–NRPS pathways representing the major biosynthetic classes. The BGCs were grouped into 828 GCFs, of which 567 (68.5%) were species-specific, indicating extensive lineage-level diversification. In contrast, several metabolite-associated biosynthetic systems were conserved across multiple species. Notably, squalestatin S1-associated BGCs occurred in all 24 species but were distributed among 15 distinct GCFs, demonstrating conservation of predicted biosynthetic capacity despite substantial variation in cluster architecture. GCFs associated with characterized antifungal metabolites, including ilicicolin H, leucinostatins, zopfiellin, sordarin, and monorden/monocillins, were also identified. Moreover, 553 GCFs (66.8%) lacked close matches to characterized MIBiG clusters and were classified as chemically unresolved, highlighting a substantial unexplored biosynthetic repertoire. Overall, these findings reveal extensive diversification alongside selective conservation of secondary-metabolite pathways across Talaromyces and provide a genomic framework for prioritizing species and BGCs for antifungal natural-product discovery and biocontrol-oriented investigation. These genome-based predictions require metabolomic and functional validation to confirm metabolite production and biological activity.
B. Chellappan, Hashem Al-Sheikh· Journal of Fungi· 0 citations
Marine-derived Streptomyces are among the most prolific producers of structurally diverse and biologically active natural products. Adaptation to unique marine environments, including deep-sea sediments, hydrothermal vents, mangrove ecosystems, marine invertebrates, and hypersaline habitats, has promoted the evolution of specialized biosynthetic systems capable of generating a broad spectrum of secondary metabolites. These metabolites include polyketides, non-ribosomal peptides (NRPs), ribosomally synthesized and post-translationally modified peptides (RiPPs), terpenoids, alkaloids, and hybrid compounds with significant antibacterial, antifungal, antiviral, antiparasitic, anti-inflammatory, and anticancer activities. Recent advances in genome sequencing, bioinformatics, genome mining, metabolomics, synthetic biology, and artificial intelligence (AI)-assisted discovery have substantially expanded marine natural product research by enabling the identification and prioritization of previously inaccessible biosynthetic gene clusters (BGCs). However, major challenges remain, including silent biosynthetic pathways, low cultivation efficiency, rediscovery of known compounds, metabolite yield instability, dereplication bottlenecks, and limited ecological interpretation. These constraints continue to impede the translation of biosynthetic potential into pharmaceutical applications. This review summarizes current strategies for marine natural product discovery and highlights emerging translational approaches integrating multi-omics technologies, pathway engineering, and AI-guided prioritization. Collectively, these advances provide a roadmap for advancing marine Streptomyces research from descriptive omics-based exploration toward experimentally validated and clinically relevant drug discovery.
M. Lertcanawanichakul, P. Bhoopong, Tuanhawanti Sahabuddeen et al.· Marine Drugs· 0 citations
Fungal species are a rich source of bioactive metabolites for agrochemical discovery. LC-MS/MS-guided molecular networking of Aspergillus japonicus led to the isolation of eight rare calbistrin-type polyketides (1-8), including three new derivatives, japonidienes J-L (1-3). Their structures were elucidated by spectroscopic analysis and computational methods. Compounds 1, 2, and 5-8 were evaluated for phytotoxicity against Eleusine indica and Amaranthus retroflexus seeds. Compounds 1 and 2 inhibited E. indica radicle elongation by 89.4% and 87.8%, respectively, comparable to glyphosate, while compounds 1, 2, and 5 inhibited A. retroflexus seedling growth more strongly than glyphosate. Integrated omics, qRT-PCR, and molecular docking/molecular dynamics simulations analyses suggested that compound 1 may affect trehalose-related metabolism through potential interaction with trehalose-6-phosphate synthase. Zebrafish embryo assays indicated relatively low developmental toxicity, supporting calbistrins as promising herbicidal leads.
Liancheng Xu, Chi Liang, Yu Chen et al.· Journal of Agricultural and...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
