Monica Ness, Karen L. Wendt, Thilini Peramuna, Demetrius I. Tillery, Jillian E. Murray, Robert H. Cichewicz* and Laura-Isobel McCall*,
{"title":"Systematic Assessment of the Impact of Targeted Selection Methods and Environment-Mimicking Culture Conditions on Fungal Natural Product Libraries","authors":"Monica Ness, Karen L. Wendt, Thilini Peramuna, Demetrius I. Tillery, Jillian E. Murray, Robert H. Cichewicz* and Laura-Isobel McCall*, ","doi":"10.1021/acs.jnatprod.6c00295","DOIUrl":"10.1021/acs.jnatprod.6c00295","url":null,"abstract":"<p >Natural products are a rich source of bioactive molecules and undiscovered chemical scaffolds with significant potential for drug discovery. Among producers of natural products, fungi are particularly promising, offering diverse metabolites and undiscovered structural motifs. Large, well-curated collections of crude extracts, or “libraries”, are central to fungal natural product discovery, serving as starting material for bioassay-guided isolation of new compounds. However, the systematic influence of fungal selection strategies, culturing methods, and environmental factors on chemical diversity remains underexplored. In this study, we analyzed several large fungal libraries to assess how geographic origin and phylogenetic classification shape fungal chemical profiles. We also evaluated whether culturing conditions that more closely mimic natural environments can enhance metabolite diversity. Our findings offer practical guidelines for optimizing fungal natural product library design, improving drug development efficiency and accessing novel chemotypes for future drug discovery.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1821–1833"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jnatprod.6c00295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147985519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anfu Wei, Chengneng Mi, Meihan Liu, Ruolan Sun, Yong Nian, Beibei Li*, Ge Liao* and Xiaoyu Tang*,
{"title":"Enzymatic C-Acylation Enables Diversification of Tetramate Antibiotic Scaffolds","authors":"Anfu Wei, Chengneng Mi, Meihan Liu, Ruolan Sun, Yong Nian, Beibei Li*, Ge Liao* and Xiaoyu Tang*, ","doi":"10.1021/acs.jnatprod.6c00215","DOIUrl":"10.1021/acs.jnatprod.6c00215","url":null,"abstract":"<p >Tetramate (pyrrolidine-2,4-dione) scaffolds are widely distributed among bacterial natural products, including metabolites produced by human-associated microorganisms, where they contribute to microbial competition and ecological fitness. Enzymatic tailoring reactions play important roles in diversifying these bioactive scaffolds; however, enzymatic C-acylation has thus far been largely restricted to Friedel–Crafts-type reactions on aromatic substrates. Here, we report the identification and characterization of a family of bacterial acyltransferases from distinct bacterial species, including <i>Streptococcus macacae</i> (<i>Sma</i>ATase), <i>Lactococcus hircilactis</i> (<i>Lh</i>ATase), <i>Priestia megaterium</i> (<i>Pm</i>ATase), and <i>Bacillus pseudomycoides</i> (<i>Bp</i>ATase). These enzymes exhibit broad tolerance toward tetramate acceptors and phenyl acyl ester donors, enabling enzymatic diversification beyond classical aromatic frameworks. Selected acylated products retained or modestly improved antibacterial activity against methicillin-resistant <i>Staphylococcus aureus</i>, highlighting the potential of this enzymatic platform for expanding the chemical space of tetramate metabolites. Together, this work establishes an enzymatic strategy for diversification of tetramate natural product scaffolds and expands the scope of enzymatic C–C bond formation in microbial natural product chemistry.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1756–1763"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhengyi Shi, Xiangli Zhao, Jiangchun Wei, Xiaosheng Tan, Zhangrong Hou, Yi Guo, Gang Chen*, Changxing Qi*, Jianping Wang* and Yonghui Zhang*,
{"title":"Spiropatuols A–H: Polycyclic Polyprenylated Acylphloroglucinols from Hypericum patulum with Activity against Concanavalin A–Induced Autoimmune Hepatitis","authors":"Zhengyi Shi, Xiangli Zhao, Jiangchun Wei, Xiaosheng Tan, Zhangrong Hou, Yi Guo, Gang Chen*, Changxing Qi*, Jianping Wang* and Yonghui Zhang*, ","doi":"10.1021/acs.jnatprod.6c00204","DOIUrl":"10.1021/acs.jnatprod.6c00204","url":null,"abstract":"<p >Eight new spiropolycyclic polyprenylated acylphloroglucinols, named spiropatuols A–H (<b>1</b>–<b>8</b>), were isolated from the traditional Chinese medicinal herb <i>Hypericum patulum</i>. The structures of compounds <b>1</b>–<b>8</b> were characterized using spectroscopic analysis, calculations of nuclear magnetic resonance chemical shifts with DP4+ probability analysis, and electronic circular dichroism calculations. Compounds <b>2</b>–<b>4</b> exhibited immunosuppressive activities in an in vitro model of concanavalin A (Con A)–induced murine splenocyte proliferation, with half-maximal inhibitory concentrations of 50, 70, and 200 nM, respectively. Furthermore, in a Con A–challenged autoimmune hepatitis mouse model, compound <b>2</b> inhibited Con A–induced activation of mice splenic lymphocytes and alleviated Con A–induced acute liver injury. These results indicate that the metabolites isolated in this study can inform the design of novel immunosuppressors for treating autoimmune hepatitis.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1764–1774"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147968714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sonia Abreu, Clara Lejeune, Colin Grunberger, Enora Jaffrezic, Marie-Joelle Virolle and Pierre Chaminade*,
{"title":"Comprehensive Lipidomic Analysis of Streptomyces by NPLC-HRMS Reveals a Previously Unknown Phospholipid Class","authors":"Sonia Abreu, Clara Lejeune, Colin Grunberger, Enora Jaffrezic, Marie-Joelle Virolle and Pierre Chaminade*, ","doi":"10.1021/acs.jnatprod.5c01603","DOIUrl":"10.1021/acs.jnatprod.5c01603","url":null,"abstract":"<p >Studies on lipids in <i>Streptomyces</i> bacteria are limited and primarily rely on thin-layer chromatography (TLC) and off-line mass spectrometry. In this article, we present an in-depth analysis of <i>Streptomyces</i> lipids, performed using normal-phase liquid chromatography coupled with high-resolution mass spectrometry (NPLC-HRMS), applied to various <i>Streptomyces</i> strains in recent collaborations. All identified lipid classes detected in the extracts are described. Numerous mass spectra are provided, offering a detailed view of the distribution of molecular species and their structural characteristics. Above all, HRMS analyses allowed us to elucidate the structure of a new class of phospholipids that had never been described before. This new phospholipid, called PIPA, was shown to result from the condensation of phosphatidylinositol (PI) and phosphatidic acid (PA) and is detected at a specific time in the <i>Streptomyces</i> cell cycle.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1655–1670"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolution-Oriented Modular Excision of Polyketide Synthases at a Splice Site of Enoylreductase Domain Yielded an Anti-Inflammatory Carboxyl Polyether","authors":"Chang Xu, Li-Li Hong, Jing Xu, Haixia Zang, Wenrui Peng, Hou-Wen Lin* and Yongjun Zhou*, ","doi":"10.1021/acs.jnatprod.6c00405","DOIUrl":"10.1021/acs.jnatprod.6c00405","url":null,"abstract":"<p >Polyketide natural products represent a major source of medicinal compounds. The majority of them are biosynthesized by the modular polyketide synthase (PKS) assembly line in <i>Streptomyces</i> spp. Due to the high sequence similarity among the coding regions of PKSs, recombination-mediated gene truncation is prevalent in PKSs. These recombination sites can be the guidelines of reprogramming PKSs for designed biosynthesis. Herein, we have discovered that a PKS module excision naturally occurred between two adjacent enoylreductase (ER) domains in the PKS assembly line of carboxyl polyether ionomycin (INO). The recombination led to significant accumulation of a two-carbon truncated product of INO, neoionomycin A, which exhibited significant anti-inflammatory activities in both zebrafish neuroinflammation and mouse colitis models. Moreover, the natural fusion site of the ER domain was successfully applied to generate the second PKS module excision, yielding another truncated product of INO. The study should represent the first instance of generating the functional hybrid PKS module via a splice junction within the ER domain, thereby adding a new reference site for the rational PKS reconstruction.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1924–1931"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structurally Diverse Secondary Metabolites from the Stem of Tinospora cordifolia and Their Anti-Inflammatory Potential on RAW264.7 Macrophages","authors":"Dixhya Rani, Diksha Saroch, Anil Bhushan, Manish Kumar Sharma, Bashir Ahmad Lone, Urvashi Dhiman, Gurleen Kour, Zabeer Ahmed* and Prasoon Gupta*, ","doi":"10.1021/acs.jnatprod.6c00126","DOIUrl":"10.1021/acs.jnatprod.6c00126","url":null,"abstract":"<p >Six new secondary metabolites were isolated from the stem extract of <i>Tinospora cordifolia</i>, including two polyoxygenated sterols, cordisterone A (<b>1</b>) and cordisterone B (<b>3</b>), two terpenes, cordipene A (<b>2</b>) and cordipene B (<b>4</b>), a <i>C</i>-glucoside, cordiside A (<b>5</b>), rare 2-(4-amino-2-hydroxybutyl) benzoic acid, cordizoic acid (<b>6</b>), and 18 (<b>7–24</b>) known compounds. Compounds <b>7</b> and <b>8</b> were isolated for the first time from this plant. Their structures, including absolute configurations, were determined by detailed examination of 1D/2D NMR, HRESIMS spectroscopic data, optical rotation, and electronic circular dichroism (ECD) calculations. Extracts, fractions, and pure compounds were evaluated for their nitric oxide inhibitory effects in lipopolysaccharide-activated RAW264.7 cells. Cordiside A (<b>5</b>) significantly inhibited nitric oxide (NO) production in murine macrophage cells with an IC<sub>50</sub> value of 3.79 ± 0.68 μM and exhibited low cytotoxicity (IC<sub>50</sub> > 50 μM), whereas <b>2</b> and <b>6</b> showed moderate activity. Cordiside A (<b>5</b>) also inhibited interleukin-6 (IL-6) and TNF-α significantly at the concentration of 12.5 μM with the IC<sub>50</sub> values of 5.12 ± 0.56 and 8.61 ± 0.69 μM, respectively. This study disclosed the discovery and structure characterization of six new compounds and the significant therapeutic potential of the new C-glycoside (<b>5</b>) in combating inflammation-related diseases.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1724–1737"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147757513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julian Schubert, Christian Geibel, Anne Berscheid, Katharina W. Wex, Giovanni Andrea Vitale, Chambers C. Hughes, Daniel Petras* and Heike Brötz-Oesterhelt*,
{"title":"Proteotoxic Stress Bioreporter Enables Mechanism-Informed Antibiotic Discovery","authors":"Julian Schubert, Christian Geibel, Anne Berscheid, Katharina W. Wex, Giovanni Andrea Vitale, Chambers C. Hughes, Daniel Petras* and Heike Brötz-Oesterhelt*, ","doi":"10.1021/acs.jnatprod.6c00112","DOIUrl":"10.1021/acs.jnatprod.6c00112","url":null,"abstract":"<p >Antibiotic resistance poses a major global health challenge, which is intensified by the decline in antibiotic discovery efforts. This highlights the urgent need for innovative antibacterial agents. Natural products remain a key source of antibiotics, yet early mechanistic insights are often lacking. Classical whole-cell screening identifies growth inhibition but provides no mechanistic information. Bioreporter strains combine bioactivity detection with preliminary mechanistic profiling; however, they remain unavailable for several promising antibiotic target areas. We developed a sensitive bioreporter that signals the induction of the heat-shock Clp-ATPase gene <i>clpE</i> in <i>Bacillus subtilis</i>. ClpE serves as a specific biomarker for proteotoxic stress, resulting from the accumulation of damaged or misfolded proteins. The self-sustained luminescence of the P<sub><i>clpE</i></sub>-lux bioreporter enables monitoring of proteotoxic stress in both solid and liquid assay formats and supports high-throughput screening. Consolidated through extensive validation with reference antibiotics, the bioreporter also identified antibacterial agents that were not previously associated with proteotoxic stress. Coupling the bioreporter with a microfractionation-based metabolomics workflow accelerated the identification of hydrophilic antibacterial metabolites from complex natural product extracts, thereby uncovering an extensive group of streptothricin derivatives, including putatively novel analogues. This study demonstrates that the P<sub><i>clpE</i></sub>-lux bioreporter is a versatile tool for mechanism-informed antibiotic discovery, enhancing the detection sensitivity and dereplication efficiency.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1698–1710"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jnatprod.6c00112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiao Yang, Sandra Tienda, Francisco M. Cazorla and Benjamin R. Clark*,
{"title":"Effect of Chain Length on the Antimicrobial Properties of Dialkylresorcinols","authors":"Jiao Yang, Sandra Tienda, Francisco M. Cazorla and Benjamin R. Clark*, ","doi":"10.1021/acs.jnatprod.6c00306","DOIUrl":"10.1021/acs.jnatprod.6c00306","url":null,"abstract":"<p >Dialkylresorcinols (DARs) are naturally occurring compounds produced in several species of the <i>Photorhabdus</i> and <i>Pseudomonas</i> bacterial genera, which are involved in modulating quorum-sensing in the producing organisms, as well as possessing significant antimicrobial properties. A range of dialkylresorcinols were synthesized, systematically varying the chain-lengths of the C-2 and C-5 alkyl chains, and the antimicrobial properties of the products assessed. Against two <i>Staphylococcus</i> test strains, medium-length alkyl chains (5–7 carbons) in both positions proved optimum for high antibiotic activity, with several derivatives displaying low micromolar activity. Activity against other test organisms was very different, with 2-hexylresorcinol (<b>11</b>) displaying the highest potency against <i>Escherichia coli</i>, <i>Pseudomonas syringae</i>, and <i>Xanthomonas campestris</i> test strains; its structure likely enables efficient membrane interaction while maintaining bioavailability.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1834–1841"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148135921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yifei Zhang, Chuanfang Zhao, Bitao Wei, Linjin Li, Pengpeng Nie, Jun Liu* and Yuguo Du,
{"title":"Total Synthesis and Structural Revision of (−)-Garvensintriol","authors":"Yifei Zhang, Chuanfang Zhao, Bitao Wei, Linjin Li, Pengpeng Nie, Jun Liu* and Yuguo Du, ","doi":"10.1021/acs.jnatprod.6c00456","DOIUrl":"10.1021/acs.jnatprod.6c00456","url":null,"abstract":"<p >The stereoselective total synthesis and structure revision of (−)-garvensintriol, a cytotoxic styryllactone from <i>Goniothalamus arvensis</i>, has been accomplished. Through meticulous synthetic efforts, single-crystal X-ray diffraction analyses, and DFT calculations, we revised the stereochemistry of C-5 and C-6 in the originally proposed structure of garvensintriol and established the correct structure as a five-membered γ-butyrolactone, rather than the previously assigned saturated δ-lactone. The revised structure of (−)-garvensintriol was unambiguously confirmed by its chemical synthesis. In addition, our revised garvensintriol displays identical spectral data with those reported for another naturally occurring styryllactone, (−)-3-deoxycardiobutanolide, suggesting that (+)-garvensintriol and (−)-3-deoxycardiobutanolide are, in fact, the same natural product.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1942–1950"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148147526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Enantiomeric Prenylated Neolignans from the Roots of Illicium verum with Analgesic Activity","authors":"Li Zou, Zhi-Hui Luo, Ying Chen, Shu-Li Duan, Qi-Hang Luo, Yu-Xiang Gao, Liang-Yan Xiao, Hong-Xia Fan, Zheng-Qun Zhou* and Hao Gao*, ","doi":"10.1021/acs.jnatprod.6c00208","DOIUrl":"10.1021/acs.jnatprod.6c00208","url":null,"abstract":"<p >Two pairs of unprecedented enantiomeric prenylated neolignans (<b>1a</b>/<b>1b</b> and <b>2a</b>/<b>2b</b>) with an unparalleled 9.2′,8.O.3′-linked skeleton were isolated from the roots of <i>Illicium verum</i>, along with three biogenetically related metabolites (<b>3a</b>/<b>3b</b> and <b>4</b>). The structures of these compounds were elucidated using spectroscopic techniques, X-ray crystallography analysis, and quantum chemical calculations. Both 2,4,5-trioxygenated phenylpropanoids (represented by <b>4</b>) and their analogues with dearomatization of the benzene ring (represented by <b>3</b>) are uncommon. Compounds <b>1a</b>/<b>1b</b> and <b>2a</b>/<b>2b</b> are likely produced by their dimerization. Inspired by the traditional effects of <i>I. verum</i>’s fruits, the analgesic activities of compounds <b>1</b>–<b>4</b> were evaluated using a glacial acetic acid-induced zebrafish pain model. The results indicated that all compounds showed different levels of analgesic activity. A major and active prenylated 2,4,5-trioxygenated phenylpropanoid with the dearomatization of the benzene ring (<b>3</b>) exhibited dose-dependent analgesic activity in a formalin-induced mouse paw licking assay. The analgesic potency of compound <b>3</b> is comparable to that of the positive drug diclofenac sodium (DCS) under the same dose (10 mg/kg). The analgesic potencies of compounds <b>3</b>, <b>3a</b>, and <b>3b</b> were also comparable under a 2 mg/kg dose. The analgesic activities of prenylated phenylpropanoids with dearomatization of the benzene ring are first reported herein.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1747–1755"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}