{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:49:34Z","timestamp":1791355774462,"version":"4.3.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    The untapped metabolome of filamentous fungi represents a profound reservoir for therapeutic lead discovery. Although genomic mining confirms an abundance of cryptic biosynthetic gene clusters (BGCs), axenic laboratory culture frequently lacks the ecological stimuli required to trigger their expression, inevitably leading to the redundant isolation of known metabolites. To circumvent this biosynthetic silencing and unlock hidden chemical diversity, strategies such as heterologous expression, the one-strain-many-compounds (OSMAC), epigenetic modulation, and microbial co-cultivation have been increasingly deployed. Herein, we harnessed an interspecies co-cultivation strategy to systematically investigate the biogenetic potential of mangrove-associated fungi belonging to the genus\n                    <jats:italic>Diaporthe<\/jats:italic>\n                    . Four fungal strains (\n                    <jats:italic>Phomopsis phyllanthicola<\/jats:italic>\n                    ZMU-32-2-1,\n                    <jats:italic>Diaporthe kyushuensis<\/jats:italic>\n                    ZMU-48-1,\n                    <jats:italic>Diaporthe phaseolorum<\/jats:italic>\n                    ZMU-49-3, and\n                    <jats:italic>Diaporthe<\/jats:italic>\n                    sp. ZMU-11) were initially isolated and purified. Subsequent co-cultivation screening revealed that strains ZMU-48-1, ZMU-32-2-1, and ZMU-11 showed altered metabolic profiles, with the appearance of novel chromatographic peaks that were not observed in their respective monocultures. Scaled-up co-fermentation and subsequent chromatographic purification led to the isolation of five structurally diverse compounds. Notably, this included two unprecedented sulfur-containing pyridine alkaloids, designated as diaridine A (1) and B (2), alongside three previously described secondary metabolites. The isolated compounds were evaluated for their antifungal properties; however, none displayed significant inhibitory activity at a concentration of 200 \u03bcg\/mL. Despite the absence of potent antifungal efficacy, these findings highlight the power of microbial crosstalk in activating the cryptic chemical space of\n                    <jats:italic>Diaporthe<\/jats:italic>\n                    species, reaffirming their potential as a robust resource for novel drug discovery.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1963522","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:50:58Z","timestamp":1791352258000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Two new sulfur-containing pyridine alkaloids from the co-culture of Diaporthe fungi"],"prefix":"10.3389","volume":"17","author":[{"given":"Ji-Xin","family":"Li","sequence":"first","affiliation":[{"name":"School of Bioengineering, Zunyi Medical University, Zhuhai","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Shan","family":"Gong","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Zunyi Medical University, Zhuhai","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Xue","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Zunyi Medical University, Zhuhai","place":["Guangdong, China"]},{"name":"Guizhou Key Laboratory of Integrated Traditional Chinese and Western Medicine, Zunyi Medical University","place":["Zhuhai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Jie","family":"Shen","sequence":"additional","affiliation":[{"name":"Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)","place":["Zhuhai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Xian","family":"Lu","sequence":"additional","affiliation":[{"name":"Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)","place":["Zhuhai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu-Juan","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Zunyi Medical University, Zhuhai","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Peng","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Zunyi Medical University, Zhuhai","place":["Guangdong, China"]},{"name":"Guizhou Key Laboratory of Integrated Traditional Chinese and Western Medicine, Zunyi Medical University","place":["Zhuhai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Zunyi Medical University, Zhuhai","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1089\/cmb.2012.0021","article-title":"SPades: A new genome assembly algorithm and its applications to single-cell sequencing.","volume":"19","author":"Bankevich","year":"2012","journal-title":"J. Comput. Biol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3158","DOI":"10.1016\/j.ejmech.2011.04.013","article-title":"3-(1,3,4-Thiadiazole-2-yl)quinoline derivatives: Synthesis, characterization and anti-microbial activity.","volume":"46","author":"Bhat","year":"2011","journal-title":"Eur. J. Med. Chem"},{"key":"B3","doi-asserted-by":"publisher","first-page":"W81","DOI":"10.1093\/nar\/gkz310","article-title":"antiSMASH 5.0: Updates to the secondary metabolite genome mining pipeline.","volume":"47","author":"Blin","year":"2019","journal-title":"Nucleic. Acids Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"R56","DOI":"10.1186\/gb-2012-13-6-r56","article-title":"Toward almost closed genomes with gapfiller.","volume":"13","author":"Boetzer","year":"2012","journal-title":"Genome. Biol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1021\/np0102713","article-title":"Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge.","volume":"64","author":"Cueto","year":"2001","journal-title":"J. Nat. Prod"},{"key":"B6","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3390\/md14050086","article-title":"Polyketides from the mangrove-derived endophytic fungus Nectria sp. HN001 and their \u03b1-glucosidase inhibitory activity.","volume":"14","author":"Cui","year":"2016","journal-title":"Mar. Drugs"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4636","DOI":"10.1093\/nar\/27.23.4636","article-title":"Improved microbial gene identification with GLIMMER.","volume":"27","author":"Delcher","year":"1999","journal-title":"Nucleic. Acids Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/ja.2008.16","article-title":"Microbial drug discovery: 80 years of progress.","volume":"62","author":"Demain","year":"2009","journal-title":"J. Antibiot"},{"key":"B9","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1186\/s13059-019-1832-y","article-title":"OrthoFinder: Phylogenetic orthology inference for comparative genomics.","volume":"20","author":"Emms","year":"2019","journal-title":"Genome. Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/s41579-018-0121-1","article-title":"Fungal secondary metabolism: Regulation, function and drug discovery.","volume":"17","author":"Keller","year":"2019","journal-title":"Nat. Rev. Microbiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1039\/d1np00070e","article-title":"Fungal-fungal co-culture: A primer for generating chemical diversity.","volume":"39","author":"Knowles","year":"2022","journal-title":"Nat. Prod. Rep"},{"key":"B12","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1101\/gr.215087.116","article-title":"Canu: Scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation.","volume":"27","author":"Koren","year":"2017","journal-title":"Genome. Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.1093\/bioinformatics\/bth315","article-title":"TigrScan and glimmerHMM: Two open source ab initio eukaryotic gene-finders.","volume":"20","author":"Majoros","year":"2004","journal-title":"Bioinformatics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1021\/acs.jnatprod.5b00450","article-title":"Citrifelins A and B, citrinin adducts with a tetracyclic framework from cocultures of marine-derived isolates of penicillium citrinum and beauveria felina.","volume":"78","author":"Meng","year":"2015","journal-title":"J. Nat. Prod"},{"key":"B15","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3389\/fmicb.2015.00299","article-title":"Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters.","volume":"6","author":"Netzker","year":"2015","journal-title":"Front. Microbiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5267","DOI":"10.1016\/j.bmc.2005.05.068","article-title":"Libertellenones A-D: Induction of cytotoxic diterpenoid biosynthesis by marine microbial competition.","volume":"13","author":"Oh","year":"2005","journal-title":"Bioorg. Med. Chem"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1363354","DOI":"10.3389\/fchem.2024.1363354","article-title":"Biologically active secondary metabolites from white-rot fungi.","volume":"12","author":"Pinar","year":"2024","journal-title":"Front. Chem"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e2020230118","DOI":"10.1073\/pnas.2020230118","article-title":"An interpreted atlas of biosynthetic gene clusters from 1,000 fungal genomes.","volume":"118","author":"Robey","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"B19","doi-asserted-by":"publisher","first-page":"14558","DOI":"10.1073\/pnas.0901870106","article-title":"Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans.","volume":"106","author":"Schroeckh","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"B20","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1021\/np980011u","article-title":"Three new metabolites from the marine yeast aureobasidium pullulans.","volume":"61","author":"Shigemori","year":"1998","journal-title":"J. Nat. Prod"},{"key":"B21","doi-asserted-by":"publisher","first-page":"D516","DOI":"10.1093\/nar\/gkae987","article-title":"OrthoDB and BUSCO update: Annotation of orthologs with wider sampling of genomes.","volume":"53","author":"Tegenfeldt","year":"2025","journal-title":"Nucleic. Acids. Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"eabo6094","DOI":"10.1126\/sciadv.abo6094","article-title":"Fungal-fungal cocultivation leads to widespread secondary metabolite alteration requiring the partial loss-of-function VeA1 protein.","volume":"8","author":"Wang","year":"2022","journal-title":"Sci. Adv"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e202402715","DOI":"10.1002\/cbdv.202402715","article-title":"Mining silent biosynthetic gene clusters for natural products in filamentous fungi.","volume":"22","author":"Wang","year":"2025","journal-title":"Chem. Biodivers"},{"key":"B24","doi-asserted-by":"publisher","first-page":"453","DOI":"10.3390\/jof9040453","article-title":"Potential of secondary metabolites of diaporthe species associated with terrestrial and marine origins.","volume":"9","author":"Wei","year":"2023","journal-title":"J. Fungi"},{"key":"B25","doi-asserted-by":"publisher","first-page":"5408","DOI":"10.1039\/c3cs35498a","article-title":"Chirality sensing using stereodynamic probes with distinct electronic circular dichroism output.","volume":"42","author":"Wolf","year":"2013","journal-title":"Chem. Soc. Rev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"464","DOI":"10.3390\/microorganisms11020464","article-title":"The potential use of fungal co-culture strategy for discovery of new secondary metabolites.","volume":"11","author":"Xu","year":"2023","journal-title":"Microorganisms"},{"key":"B27","doi-asserted-by":"publisher","first-page":"217","DOI":"10.3390\/microorganisms9020217","article-title":"Bioactive secondary metabolites of the genus diaporthe and anamorph phomopsis from terrestrial and marine habitats and endophytes: 2010-2019.","volume":"9","author":"Xu","year":"2021","journal-title":"Microorganisms"},{"key":"B28","doi-asserted-by":"publisher","first-page":"4146","DOI":"10.1021\/jo100496f","article-title":"The relationship between the CD cotton effect and the absolute configuration of FD-838 and its seven stereoisomers.","volume":"75","author":"Yamada","year":"2010","journal-title":"J. Org. Chem"},{"key":"B29","doi-asserted-by":"publisher","first-page":"4063","DOI":"10.1021\/jf405437k","article-title":"Synthesis and antifungal activity of nicotinamide derivatives as succinate dehydrogenase inhibitors.","volume":"62","author":"Ye","year":"2014","journal-title":"J. Agric. Food. Chem"},{"key":"B30","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.phytol.2020.11.017","article-title":"Three new diterpenoid alkaloids from delphinium tatsienense.","volume":"41","author":"Yin","year":"2021","journal-title":"Phytochem. Lett"},{"key":"B31","doi-asserted-by":"publisher","first-page":"663924","DOI":"10.3389\/fmicb.2021.663924","article-title":"Coculture, an efficient biotechnology for mining the biosynthesis potential of macrofungi via interspecies interactions.","volume":"12","author":"Yu","year":"2021","journal-title":"Front. Microbiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/s42269-024-01199-x","article-title":"Progress in endophytic fungi secondary metabolites: Biosynthetic gene cluster reactivation and advances in metabolomics.","volume":"48","author":"Zakariyah","year":"2024","journal-title":"Bull. Natl. Res. Cent"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.4268\/cjcmm20151217","article-title":"A new lactone derivative from plant endophytic fungus Periconia sp. F-31.","volume":"40","author":"Zhang","year":"2015","journal-title":"China J. Chin. Mater. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"653","DOI":"10.3390\/jof10090653","article-title":"Global analysis of natural products biosynthetic diversity encoded in fungal genomes.","volume":"10","author":"Zhang","year":"2024","journal-title":"J. Fungi"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1604639","DOI":"10.3389\/fmicb.2025.1604639","article-title":"Genome mining and OSMAC strategies unveil diverse secondary metabolites from the endophytic fungus diaporthe kyushuensis ZMU-48-1 with antifungal activity.","volume":"16","author":"Zheng","year":"2025","journal-title":"Front. Microbiol"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1963522\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:50:59Z","timestamp":1791352259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1963522\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":35,"alternative-id":["10.3389\/fmicb.2026.1963522"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1963522","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"article-number":"1963522"}}