Biyan Chen, Emre F Bülbül, SeoungGun Bang, Hannah A Minas, Kenan A J Bozhüyük
Covering: up to 2025.Non-ribosomal peptide synthetases and polyketide synthases are modular biosynthetic systems that produce structurally diverse and pharmacologically potent natural products, including antibiotics, immunosuppressants, and anticancer agents. Their programmable architecture has long inspired efforts in biosynthetic re-engineering. This review highlights recent advances that are transforming non-ribosomal peptide synthetase and polyketide synthase systems into versatile platforms for rational design. We discuss progress in genome mining, high-throughput screening, and dereplication, alongside emerging tools from synthetic biology and computational modeling. Particular focus is given to structure-based approaches-such as homology modeling, molecular docking, and molecular dynamics simulations-as well as deep learning strategies for enzyme prediction and design. Rather than replacing classical techniques, these computational methods now complement and extend them, enabling accelerating the discovery and assembly of tailor-made natural product analogs.
{"title":"Toward a unified pipeline for natural product discovery: tools and strategies for NRPS and PKS pathway exploration and engineering.","authors":"Biyan Chen, Emre F Bülbül, SeoungGun Bang, Hannah A Minas, Kenan A J Bozhüyük","doi":"10.1039/d5np00041f","DOIUrl":"10.1039/d5np00041f","url":null,"abstract":"<p><p>Covering: up to 2025.Non-ribosomal peptide synthetases and polyketide synthases are modular biosynthetic systems that produce structurally diverse and pharmacologically potent natural products, including antibiotics, immunosuppressants, and anticancer agents. Their programmable architecture has long inspired efforts in biosynthetic re-engineering. This review highlights recent advances that are transforming non-ribosomal peptide synthetase and polyketide synthase systems into versatile platforms for rational design. We discuss progress in genome mining, high-throughput screening, and dereplication, alongside emerging tools from synthetic biology and computational modeling. Particular focus is given to structure-based approaches-such as homology modeling, molecular docking, and molecular dynamics simulations-as well as deep learning strategies for enzyme prediction and design. Rather than replacing classical techniques, these computational methods now complement and extend them, enabling accelerating the discovery and assembly of tailor-made natural product analogs.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Covering up to 2024Drug resistance is a serious and growing problem, and new small molecules are needed for a wide variety of clinical and agricultural applications. Natural products, encoded by biosynthetic gene clusters, have consistently been a source of chemical diversity for finely tuned interactions with a range of molecular targets of interest. However, many gene clusters are not transcriptionally active, making heterologous expression in a different host strain a useful tool to access bioactive small molecules. Burkholderia spp. bacteria hold promise as heterologous hosts because of their intrinsic natural product capabilities. In this review, we summarize natural products successfully isolated from Burkholderia spp. heterologous hosts up until 2024. We then compare the hosts that have been tested and discuss ongoing development efforts to improve access to new natural products in titers sufficient for drug development and industrial applications.
{"title":"The development of <i>Burkholderia</i> bacteria as heterologous hosts.","authors":"Stephanie C Heard, Alessandra S Eustáquio","doi":"10.1039/d5np00024f","DOIUrl":"10.1039/d5np00024f","url":null,"abstract":"<p><p>Covering up to 2024Drug resistance is a serious and growing problem, and new small molecules are needed for a wide variety of clinical and agricultural applications. Natural products, encoded by biosynthetic gene clusters, have consistently been a source of chemical diversity for finely tuned interactions with a range of molecular targets of interest. However, many gene clusters are not transcriptionally active, making heterologous expression in a different host strain a useful tool to access bioactive small molecules. <i>Burkholderia</i> spp. bacteria hold promise as heterologous hosts because of their intrinsic natural product capabilities. In this review, we summarize natural products successfully isolated from <i>Burkholderia</i> spp. heterologous hosts up until 2024. We then compare the hosts that have been tested and discuss ongoing development efforts to improve access to new natural products in titers sufficient for drug development and industrial applications.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eilidh G. Young, Freda F. Li and Margaret A. Brimble
Covering: 2010 to December 2024
Traditional Chinese medicine is an ancient knowledge base of therapeutic plants and preparations. Today, the isolation of bioactive natural products from traditional Chinese medicine is a valuable tool to identify new scaffolds for drug discovery. One such scaffold, the spiroketal moiety, is widespread in bioactive natural products, often crucial to the bioactivity of the compound. The convergent evolution of the spiroketal moiety in natural products arising from diverse phylogenetic and biosynthetic origins is a hallmark of the biological importance of this moiety. This review aims to highlight the diverse biosynthetic origins and ensuant structural diversity of spiroketal natural products isolated from traditional Chinese medicine, along with their potent and wide array of biological activities, and synthetic approaches to access these natural products to date.
{"title":"Spiroketal natural products isolated from traditional Chinese medicine: isolation, biological activity, biosynthesis, and synthesis","authors":"Eilidh G. Young, Freda F. Li and Margaret A. Brimble","doi":"10.1039/D5NP00035A","DOIUrl":"10.1039/D5NP00035A","url":null,"abstract":"<p>Covering: 2010 to December 2024</p><p>Traditional Chinese medicine is an ancient knowledge base of therapeutic plants and preparations. Today, the isolation of bioactive natural products from traditional Chinese medicine is a valuable tool to identify new scaffolds for drug discovery. One such scaffold, the spiroketal moiety, is widespread in bioactive natural products, often crucial to the bioactivity of the compound. The convergent evolution of the spiroketal moiety in natural products arising from diverse phylogenetic and biosynthetic origins is a hallmark of the biological importance of this moiety. This review aims to highlight the diverse biosynthetic origins and ensuant structural diversity of spiroketal natural products isolated from traditional Chinese medicine, along with their potent and wide array of biological activities, and synthetic approaches to access these natural products to date.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" 11","pages":" 1786-1810"},"PeriodicalIF":10.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin Philmus, Nicole E Avalon, Yousong Ding, Drew T Doering, Alessandra S Eustáquio, William H Gerwick, Hendrik Luesch, Jimmy Orjala, Shaz Sutherland, Arnaud Taton, Daniel Udwary
Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges.
{"title":"Green genes from blue greens: challenges and solutions to unlocking the potential of cyanobacteria in drug discovery.","authors":"Benjamin Philmus, Nicole E Avalon, Yousong Ding, Drew T Doering, Alessandra S Eustáquio, William H Gerwick, Hendrik Luesch, Jimmy Orjala, Shaz Sutherland, Arnaud Taton, Daniel Udwary","doi":"10.1039/d5np00016e","DOIUrl":"10.1039/d5np00016e","url":null,"abstract":"<p><p>Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
De-Gao Wang , Jia-Qi Hu , Chao-Yi Wang , Teng Liu , Yue-Zhong Li , Changsheng Wu
Covering: 2000. 01 to 2025. 03
The soaring demand for novel drugs has led to an increase in the requirement for smart methods to aid in the exploration of microbial natural products (NPs). Cutting-edge metabolomics excels at prompt identification of compounds from complex mixtures and accordingly accelerates the targeted discovery process. Although MS-based metabolomics has become a staple in this field, the utilization of NMR-based metabolomics has severely trailed in comparison. Herein, we summarize the key methodological advancements in 1D and 2D NMR techniques in the past two decades, especially for the invention of computational technologies and/or introduction of artificial intelligence for automated data processing, which significantly strengthen the ability of NMR-based metabolomics to analyze crude microbial extracts. Preliminary fractionation is advocated to deconvolute samples and thus enhance detection sensitivity towards minor components overshadowed by a complex matrix. Particularly, the synergistic application of NMR-based metabolomics and genomics provides an expedient approach to correlate biosynthetic gene clusters with cognate metabolites, greatly improving the efficiency of dereplication and, thus, targeted discovery of novel compounds. A variety of microbial NPs involving distinct chemical skeletons and/or biosynthetic logics are enumerated to prove the genuine prowess of NMR-based metabolomics. Overall, this review aims to encourage the broader adoption of NMR-based metabolomics in the realm of microbial NP research.
{"title":"Exploring microbial natural products through NMR-based metabolomics","authors":"De-Gao Wang , Jia-Qi Hu , Chao-Yi Wang , Teng Liu , Yue-Zhong Li , Changsheng Wu","doi":"10.1039/d4np00065j","DOIUrl":"10.1039/d4np00065j","url":null,"abstract":"<div><div>Covering: 2000. 01 to 2025. 03</div></div><div><div>The soaring demand for novel drugs has led to an increase in the requirement for smart methods to aid in the exploration of microbial natural products (NPs). Cutting-edge metabolomics excels at prompt identification of compounds from complex mixtures and accordingly accelerates the targeted discovery process. Although MS-based metabolomics has become a staple in this field, the utilization of NMR-based metabolomics has severely trailed in comparison. Herein, we summarize the key methodological advancements in 1D and 2D NMR techniques in the past two decades, especially for the invention of computational technologies and/or introduction of artificial intelligence for automated data processing, which significantly strengthen the ability of NMR-based metabolomics to analyze crude microbial extracts. Preliminary fractionation is advocated to deconvolute samples and thus enhance detection sensitivity towards minor components overshadowed by a complex matrix. Particularly, the synergistic application of NMR-based metabolomics and genomics provides an expedient approach to correlate biosynthetic gene clusters with cognate metabolites, greatly improving the efficiency of dereplication and, thus, targeted discovery of novel compounds. A variety of microbial NPs involving distinct chemical skeletons and/or biosynthetic logics are enumerated to prove the genuine prowess of NMR-based metabolomics. Overall, this review aims to encourage the broader adoption of NMR-based metabolomics in the realm of microbial NP research.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1459-1488"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Covering: This review summarizes recent advances in the discovery, biosynthesis, and bioactivity of RiPP-derived lipopeptides, covering studies published up to 2024.
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse superfamily of natural products unified by a common biosynthetic logic: The peptide backbone is genetically encoded, and the translated precursor peptide undergoes a series of post-translational modifications catalyzed by maturase enzymes to produce the final bioactive compound. Despite their structural complexity, RiPPs are encoded by relatively small biosynthesis gene clusters. RiPP maturase enzymes are diverse and often promiscuous, offering significant biotechnological potential. However, their lack of conserved features makes genome-based discovery of novel RiPPs challenging. Recent advances in biosynthetic understanding and genome mining techniques have led to the identification of numerous uncharacterized RiPP biosynthetic gene clusters, often flanked by genes encoding non-RiPP moieties, in microbial genomes. Leveraging this information, a new class of natural products, hybrids of RiPPs and non-RiPP elements, has recently been discovered. Among them, RiPPs bearing fatty acyl groups, referred to as RiPP-derived lipopeptides, represent a newly emerging class of lipopeptide natural products with significant antimicrobial activity.
{"title":"Recent advances in discovery and biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPP)-derived lipopeptides","authors":"Shumpei Asamizu","doi":"10.1039/d5np00042d","DOIUrl":"10.1039/d5np00042d","url":null,"abstract":"<div><div>Covering: This review summarizes recent advances in the discovery, biosynthesis, and bioactivity of RiPP-derived lipopeptides, covering studies published up to 2024.</div></div><div><div>Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse superfamily of natural products unified by a common biosynthetic logic: The peptide backbone is genetically encoded, and the translated precursor peptide undergoes a series of post-translational modifications catalyzed by maturase enzymes to produce the final bioactive compound. Despite their structural complexity, RiPPs are encoded by relatively small biosynthesis gene clusters. RiPP maturase enzymes are diverse and often promiscuous, offering significant biotechnological potential. However, their lack of conserved features makes genome-based discovery of novel RiPPs challenging. Recent advances in biosynthetic understanding and genome mining techniques have led to the identification of numerous uncharacterized RiPP biosynthetic gene clusters, often flanked by genes encoding non-RiPP moieties, in microbial genomes. Leveraging this information, a new class of natural products, hybrids of RiPPs and non-RiPP elements, has recently been discovered. Among them, RiPPs bearing fatty acyl groups, referred to as RiPP-derived lipopeptides, represent a newly emerging class of lipopeptide natural products with significant antimicrobial activity.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1622-1638"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyun Su Kim , Ahmed H. E. Hassan , Kyuho Moon , Jaehoon Sim
Covering: up to 2025
Amino acids constitute the essential components of biological systems. Over the recent years, there has been a growing interest in exploring amino acid metabolism as a source of novel druggable targets for intractable diseases such as cancer, metabolic disorders, and degenerative diseases. Culminating research has unveiled novel therapeutic targets associated with amino acid metabolism, including glutamine, cysteine, arginine, and tryptophan metabolism. The pursuit of therapeutic drug targets has resulted in the discovery of potential modulators showing promise for the development of new drug candidates. Many of these modulators have been derived from natural products, employing diverse methods such as traditional medical knowledge, high-throughput screening, and bioinformatics approaches. Based on these discoveries, a variety of synthetic analogues have been developed to improve pharmacological profiles, target selectivity, and drug-like properties. Structural optimization of natural product scaffolds, including derivatization, bioisostere incorporation, and prodrug strategies, has enabled the rational design of potent inhibitors targeting amino acid metabolism. These efforts have expanded the utility of naturally occurring inhibitors, offering enhanced efficacy and therapeutic potential. In this review, we systematically categorize natural products that target enzymes involved in amino acid metabolism, highlighting the recent advances in their development as medicinal agents. This work aims to provide a valuable resource for researchers by outlining the therapeutic potential of natural products and identifying opportunities for future investigation.
{"title":"Natural products targeting the metabolism of amino acids: from discovery to synthetic development†","authors":"Hyun Su Kim , Ahmed H. E. Hassan , Kyuho Moon , Jaehoon Sim","doi":"10.1039/d5np00039d","DOIUrl":"10.1039/d5np00039d","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>Amino acids constitute the essential components of biological systems. Over the recent years, there has been a growing interest in exploring amino acid metabolism as a source of novel druggable targets for intractable diseases such as cancer, metabolic disorders, and degenerative diseases. Culminating research has unveiled novel therapeutic targets associated with amino acid metabolism, including glutamine, cysteine, arginine, and tryptophan metabolism. The pursuit of therapeutic drug targets has resulted in the discovery of potential modulators showing promise for the development of new drug candidates. Many of these modulators have been derived from natural products, employing diverse methods such as traditional medical knowledge, high-throughput screening, and bioinformatics approaches. Based on these discoveries, a variety of synthetic analogues have been developed to improve pharmacological profiles, target selectivity, and drug-like properties. Structural optimization of natural product scaffolds, including derivatization, bioisostere incorporation, and prodrug strategies, has enabled the rational design of potent inhibitors targeting amino acid metabolism. These efforts have expanded the utility of naturally occurring inhibitors, offering enhanced efficacy and therapeutic potential. In this review, we systematically categorize natural products that target enzymes involved in amino acid metabolism, highlighting the recent advances in their development as medicinal agents. This work aims to provide a valuable resource for researchers by outlining the therapeutic potential of natural products and identifying opportunities for future investigation.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1575-1621"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gahyeon Kim , Dukwon Lee , Ji Hun Kim , Seong Do Kim , Hongki Kim , Jae Heon Kim , Sung Sun Yim , Soo-Jin Yeom , Jay D. Keasling , Byung-Kwan Cho
Covering: 2020 to 2025
Natural products remain indispensable sources of therapeutic and bioactive compounds, yet traditional discovery strategies are constrained by compound rediscovery. Modular biosynthetic enzymes, such as type I polyketide synthases (PKSs) and type A non-ribosomal peptide synthetases (NRPSs), offer promising platforms for combinatorial biosynthesis owing to their programmable architectures. However, practical implementation is frequently limited by inter-modular incompatibility and domain-specific interactions. This review highlights recent advances in modular enzyme assembly enabled by synthetic interfaces-including cognate docking domains, synthetic coiled-coils, SpyTag/SpyCatcher, and split inteins-which function as orthogonal, standardized connectors to facilitate post-translational complex formation. These interfaces support rational investigations into substrate specificity, module compatibility, and pathway derivatization as well as general enzyme clustering applications beyond PKS and NRPS systems. Synthetic interfaces can be integrated with computational tools to support a more systematic and scalable framework for modular enzyme engineering by providing predictive insights into domain compatibility and interface design. These approaches within iterative design-build-test-learn workflows can accelerate the programmable assembly of biosynthetic systems and expand the accessible chemical space for natural products.
{"title":"Engineering modular enzyme assembly: synthetic interface strategies for natural products biosynthesis applications","authors":"Gahyeon Kim , Dukwon Lee , Ji Hun Kim , Seong Do Kim , Hongki Kim , Jae Heon Kim , Sung Sun Yim , Soo-Jin Yeom , Jay D. Keasling , Byung-Kwan Cho","doi":"10.1039/d5np00027k","DOIUrl":"10.1039/d5np00027k","url":null,"abstract":"<div><div>Covering: 2020 to 2025</div></div><div><div>Natural products remain indispensable sources of therapeutic and bioactive compounds, yet traditional discovery strategies are constrained by compound rediscovery. Modular biosynthetic enzymes, such as type I polyketide synthases (PKSs) and type A non-ribosomal peptide synthetases (NRPSs), offer promising platforms for combinatorial biosynthesis owing to their programmable architectures. However, practical implementation is frequently limited by inter-modular incompatibility and domain-specific interactions. This review highlights recent advances in modular enzyme assembly enabled by synthetic interfaces-including cognate docking domains, synthetic coiled-coils, SpyTag/SpyCatcher, and split inteins-which function as orthogonal, standardized connectors to facilitate post-translational complex formation. These interfaces support rational investigations into substrate specificity, module compatibility, and pathway derivatization as well as general enzyme clustering applications beyond PKS and NRPS systems. Synthetic interfaces can be integrated with computational tools to support a more systematic and scalable framework for modular enzyme engineering by providing predictive insights into domain compatibility and interface design. These approaches within iterative design-build-test-learn workflows can accelerate the programmable assembly of biosynthetic systems and expand the accessible chemical space for natural products.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1489-1506"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paolo Monciardini , Matteo Simone , Marianna Iorio , Sonia I. Maffioli , Margherita Sosio , Stefano Donadio
Covering: 2013 to 2023
In this review, we analyzed the scientific literature of the period 2013–2023 that reported novel specialized metabolites from the Actinomycetes, one of the most prolific producers of natural products. The discovered metabolites were categorized on the basis of their chemical originality into two groups: variants of known molecules, or original metabolites. In addition, we subdivided the approaches used to discover these metabolites into four categories: bioassay-based screening, genome mining, metabolome mining, or combinations thereof. We present selected examples of the different approaches used and the resulting original metabolites. Finally, we measure the overall trends of discovery in terms of approaches, of the frequency of original metabolites and of the major biosynthetic classes that have been described. Overall, our analysis indicates that new metabolites continue to be discovered from Actinomycetes at a relatively constant rate and that the frequency of original metabolites seems to be approach-independent and relatively constant within the analyzed time period.
{"title":"Trends in metabolite discovery from Actinomycetes†","authors":"Paolo Monciardini , Matteo Simone , Marianna Iorio , Sonia I. Maffioli , Margherita Sosio , Stefano Donadio","doi":"10.1039/d4np00075g","DOIUrl":"10.1039/d4np00075g","url":null,"abstract":"<div><div>Covering: 2013 to 2023</div></div><div><div>In this review, we analyzed the scientific literature of the period 2013–2023 that reported novel specialized metabolites from the <em>Actinomycetes</em>, one of the most prolific producers of natural products. The discovered metabolites were categorized on the basis of their chemical originality into two groups: variants of known molecules, or original metabolites. In addition, we subdivided the approaches used to discover these metabolites into four categories: bioassay-based screening, genome mining, metabolome mining, or combinations thereof. We present selected examples of the different approaches used and the resulting original metabolites. Finally, we measure the overall trends of discovery in terms of approaches, of the frequency of original metabolites and of the major biosynthetic classes that have been described. Overall, our analysis indicates that new metabolites continue to be discovered from <em>Actinomycetes</em> at a relatively constant rate and that the frequency of original metabolites seems to be approach-independent and relatively constant within the analyzed time period.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1533-1547"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Richard Lewis , Richard Hammond , Mark Wilkinson , Nick Allenby
Covering: up to 2025
Bacterial natural products have long been the foundation for many therapeutic agents. However, traditional culture-based approaches to discovering these products have been deprioritised by pharmaceutical companies, primarily due to the high rates of rediscovery. To revitalise the pipeline of new drugs, especially antibiotics-an area where natural products have historically played a crucial role-new technologies are essential. Culture-independent, or metagenomic, techniques combined with long-read sequencing technologies are now enabling the identification of novel biosynthetic gene clusters (BGCs). When paired with the heterologous expression of DNA extracted directly from environmental samples (eDNA), these approaches may provide access to untapped microbial biosynthetic diversity. This review explores industrial screening for new compounds and examines how modern technologies such as metagenomics, in situ cultivation, and pico-droplet-based screening are advancing the search for novel natural products. These approaches have the potential to greatly expand the discovery of new bioactive compounds, helping to address the growing need for new therapeutic agents.
{"title":"Technological developments driving industrial natural product discovery","authors":"Richard Lewis , Richard Hammond , Mark Wilkinson , Nick Allenby","doi":"10.1039/d4np00072b","DOIUrl":"10.1039/d4np00072b","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>Bacterial natural products have long been the foundation for many therapeutic agents. However, traditional culture-based approaches to discovering these products have been deprioritised by pharmaceutical companies, primarily due to the high rates of rediscovery. To revitalise the pipeline of new drugs, especially antibiotics-an area where natural products have historically played a crucial role-new technologies are essential. Culture-independent, or metagenomic, techniques combined with long-read sequencing technologies are now enabling the identification of novel biosynthetic gene clusters (BGCs). When paired with the heterologous expression of DNA extracted directly from environmental samples (eDNA), these approaches may provide access to untapped microbial biosynthetic diversity. This review explores industrial screening for new compounds and examines how modern technologies such as metagenomics, <em>in situ</em> cultivation, and pico-droplet-based screening are advancing the search for novel natural products. These approaches have the potential to greatly expand the discovery of new bioactive compounds, helping to address the growing need for new therapeutic agents.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1507-1532"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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