{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:13:11Z","timestamp":1792498391167,"version":"4.5.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Microbial co-cultivation is employed for awakening silent biosynthetic gene clusters (BGCs) to enhance chemical diversity. However, the selection of appropriate partners for co-cultivation remains a challenge. Furthermore, competitive interactions involving the suppression of BGCs or upregulation of known, functional metabolite(s) during co-cultivation efforts is also common. Herein, we performed an alternative approach for targeted selection of the best co-cultivation pair. Eight marine sediment-derived fungi were classified as strong or weak, based on their anti-phytopathogenic potency. The fungi were co-cultured systematically and analyzed for their chemical profiles and anti-phytopathogenic activity. Based on enhanced bioactivity and a significantly different metabolite profile including the appearance of a co-culture specific cluster, the co-culture of Plenodomus influorescens (strong) and Pyrenochaeta nobilis (weak) was prioritized for chemical investigation. Large-scale co-cultivation resulted in isolation of five polyketide type compounds: two 12-membered macrolides, dendrodolide E (1) and its new analog dendrodolide N (2), as well as two rare azaphilones spiciferinone (3) and its new analog 8a-hydroxy-spiciferinone (4). A well-known bis-naphtho-\u03b3-pyrone type mycotoxin, cephalochromin (5), whose production was specifically enhanced in the co-culture, was also isolated. Chemical structures of compounds 1\u20135 were elucidated by NMR, HRMS and [\u03b1]      D 20      analyses. Compound 5 showed the strongest anti-phytopathogenic activity against Xanthomonas campestris and Phytophthora infestans with IC50 values of 0.9 and 1.7 \u00b5g\/mL, respectively.<\/jats:p>","DOI":"10.3390\/md18020073","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T10:36:02Z","timestamp":1579775762000},"page":"73","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Design of Fungal Co-Cultivation Based on Comparative Metabolomics and Bioactivity for Discovery of Marine Fungal Agrochemicals"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3567-4067","authenticated-orcid":false,"given":"Ernest","family":"Oppong-Danquah","sequence":"first","affiliation":[{"name":"GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Budnicka","sequence":"additional","affiliation":[{"name":"GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6522-2964","authenticated-orcid":false,"given":"Martina","family":"Bl\u00fcmel","sequence":"additional","affiliation":[{"name":"GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7841-6271","authenticated-orcid":false,"given":"Deniz","family":"Tasdemir","sequence":"additional","affiliation":[{"name":"GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany"},{"name":"Faculty of Mathematics and Natural Science, Kiel University, Christian-Albrechts-Platz 4, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1080\/14786419.2015.1041140","article-title":"Natural products as sources of new fungicides (II): Antiphytopathogenic activity of 2,4-dihydroxyphenyl ethanone derivatives","volume":"30","author":"Nandinsuren","year":"2015","journal-title":"Nat. Prod. Res."},{"key":"ref_2","first-page":"148","article-title":"Chemical pesticides and human health: The urgent need for a new concept in agriculture","volume":"4","author":"Maipas","year":"2016","journal-title":"Front. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/fes3.108","article-title":"Pesticides, environment, and food safety","volume":"6","author":"Carvalho","year":"2017","journal-title":"Food Energy Secur."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/bs.aambs.2014.09.001","article-title":"The evolution of fungicide resistance","volume":"90","author":"Lucas","year":"2015","journal-title":"Adv. Appl. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/mpp.12189","article-title":"The toolbox of Trichoderma spp. in the biocontrol of Botrytis cinerea disease","volume":"16","author":"Vos","year":"2015","journal-title":"Mol. Plant Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-06202-4","article-title":"Strobilurin biosynthesis in Basidiomycete fungi","volume":"9","author":"Nofiani","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/443904a","article-title":"Drugs from the deep","volume":"443","author":"Marris","year":"2006","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-28473-z","article-title":"Genome sequencing and analyses of two marine fungi from the North Sea unraveled a plethora of novel biosynthetic gene clusters","volume":"8","author":"Kumar","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/nrmicro1286","article-title":"Fungal secondary metabolism\u2014From biochemistry to genomics","volume":"3","author":"Keller","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.tim.2017.11.004","article-title":"From axenic to mixed cultures: Technological advances accelerating a paradigm shift in microbiology","volume":"26","author":"Nai","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.3390\/md12021043","article-title":"Co-cultivation\u2014A powerful emerging tool for enhancing the chemical diversity of microorganisms","volume":"12","author":"Marmann","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.biotechadv.2015.06.003","article-title":"Elicitation of secondary metabolism in actinomycetes","volume":"33","author":"Abdelmohsen","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nrmicro2832","article-title":"Microbial interactions: From networks to models","volume":"10","author":"Faust","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5267","DOI":"10.1016\/j.bmc.2005.05.068","article-title":"Libertellenones A\u2013D: Induction of cytotoxic diterpenoid biosynthesis by marine microbial competition","volume":"13","author":"Oh","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1021\/np060381f","article-title":"Induced production of emericellamides A and B from the marine-derived fungus Emericella sp. in competing co-culture","volume":"70","author":"Oh","year":"2007","journal-title":"J. Nat. Prod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2180-14-114","article-title":"Functional characterization of a Penicillium chrysogenum mutanase gene induced upon co-cultivation with Bacillus subtilis","volume":"14","author":"Bajaj","year":"2014","journal-title":"BMC Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.chroma.2013.01.098","article-title":"Detection of metabolite induction in fungal co-cultures on solid media by high-throughput differential ultra-high pressure liquid chromatography-time-of-flight mass spectrometry fingerprinting","volume":"1292","author":"Bertrand","year":"2013","journal-title":"J. Chromatogr. A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.mib.2018.04.002","article-title":"Microbial interactions trigger the production of antibiotics","volume":"45","author":"Netzker","year":"2018","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","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. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1021\/np200255f","article-title":"Induced production of N-formyl alkaloids from Aspergillus fumigatus by co-culture with Streptomyces peucetius","volume":"74","author":"Zuck","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_21","first-page":"1","article-title":"Molecular networking-based metabolome and bioactivity analyses of marine-adapted fungi co-cultivated with phytopathogens","volume":"9","author":"Parrot","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/CAD.0000000000000423","article-title":"Penicillium spp.: Prolific producer for harnessing cytotoxic secondary metabolites","volume":"28","author":"Koul","year":"2017","journal-title":"Anti Cancer Drugs"},{"key":"ref_23","unstructured":"Buckingham, J. (2019, November 01). Dictionary of Natural Products (on-Line Web Edition). Available online: http:\/\/www.chemnetbase.com."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zheng, Y.-Y., Liang, Z.-Y., Shen, N.-X., Liu, W.-L., Zhou, X.-J., Fu, X.-M., Chen, M., and Wang, C.-Y. (2019). New naphtho-\u03b3-pyrones isolated from marine-derived fungus Penicillium sp. HK1-22 and their antimicrobial activities. Mar. Drugs, 17.","DOI":"10.3390\/md17060322"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1021\/jo00941a049","article-title":"Bruceantin, a new potent antileukemic simaroubolide from Brucea antidysenterica","volume":"38","author":"Kupchan","year":"1973","journal-title":"J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7030","DOI":"10.1021\/jo400861j","article-title":"Structure, absolute configuration, and conformational study of 12-membered macrolides from the fungus Dendrodochium sp. associated with the sea cucumber Holothuria nobilis Selenka","volume":"78","author":"Sun","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0031-9422(91)83016-E","article-title":"Spiciferinone, an azaphilone phytotoxin produced by the fungus Cochliobolus spicifer","volume":"31","author":"Nakajima","year":"1992","journal-title":"Phytochemistry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1002\/ejoc.200801083","article-title":"Pseudoanguillosporin A and B: Two new isochromans isolated from the endophytic fungus Pseudoanguillospora sp.","volume":"2009","author":"Kock","year":"2009","journal-title":"Eur. J. Org. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1248\/cpb.36.146","article-title":"Further characterization of seven bis (naphtho-\u03b3-pyrone) congeners of ustilaginoidins, coloring matters of Claviceps virens (Ustilaginoidea virens)","volume":"36","author":"Koyama","year":"1988","journal-title":"Chem. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/nchembio.739","article-title":"Microbial metabolic exchange\u2014The chemotype-to-phenotype link","volume":"8","author":"Phelan","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1021\/np400761g","article-title":"Tetramic acid analogues produced by coculture of Saccharopolyspora erythraea with Fusarium pallidoroseum","volume":"77","author":"Whitt","year":"2014","journal-title":"J. Nat. Prod."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chamoun, R., Aliferis, K.A., and Jabaji, S. (2015). Identification of signatory secondary metabolites during mycoparasitism of Rhizoctonia solani by Stachybotrys elegans. Front. Microbiol., 6.","DOI":"10.3389\/fmicb.2015.00353"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11054","DOI":"10.1073\/pnas.1504076112","article-title":"Socially mediated induction and suppression of antibiosis during bacterial coexistence","volume":"112","author":"Abrudan","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/j.tetlet.2013.03.005","article-title":"Induced production of depsipeptides by co-culturing Fusarium tricinctum and Fusarium begoniae","volume":"54","author":"Wang","year":"2013","journal-title":"Tetrahedron Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmicb.2017.00649","article-title":"Co-culturing of fungal strains against Botrytis cinerea as a model for the induction of chemical diversity and therapeutic agents","volume":"8","author":"Serrano","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1021\/np400258f","article-title":"De novo production of metabolites by fungal co-culture of Trichophyton rubrum and Bionectria ochroleuca","volume":"76","author":"Bertrand","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmicb.2018.01156","article-title":"Current trends and potential applications of microbial interactions for human welfare","volume":"9","author":"Tshikantwa","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7169","DOI":"10.3390\/molecules19067169","article-title":"Bis-naphtho-\u03b3-pyrones from fungi and their bioactivities","volume":"19","author":"Lu","year":"2014","journal-title":"Molecules"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1021\/np400517g","article-title":"Cephalochromin induces G0\/G1 cell cycle arrest and apoptosis in A549 human non-small-cell lung cancer cells by inflicting mitochondrial disruption","volume":"77","author":"Hsiao","year":"2014","journal-title":"J. Nat. Prod."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1021\/ja00055a023","article-title":"Macrolide biosynthesis. 7. Incorporation of polyketide chain elongation intermediates into methymycin","volume":"115","author":"Cane","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"635","DOI":"10.7164\/antibiotics.54.635","article-title":"Cladospolide D, a new 12-membered macrolide antibiotic produced by Cladosporium sp. FT-0012","volume":"54","author":"Zhang","year":"2001","journal-title":"J. Antibiot."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3390\/md204164","article-title":"Sporiolides A and B, new cytotoxic twelve-membered macrolides from a marine-derived fungus Cladosporium species","volume":"2","author":"Shigemori","year":"2004","journal-title":"Mar. Drugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1039\/b704420h","article-title":"Polyketides, proteins and genes in fungi: Programmed nano-machines begin to reveal their secrets","volume":"5","author":"Cox","year":"2007","journal-title":"Org. Biomol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s11101-010-9171-3","article-title":"Azaphilones: A class of fungal metabolites with diverse biological activities","volume":"9","author":"Osmanova","year":"2010","journal-title":"Phytochem. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/nbt.2377","article-title":"A cross-platform toolkit for mass spectrometry and proteomics","volume":"30","author":"Chambers","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1093\/nar\/gku436","article-title":"CFM-ID: A web server for annotation, spectrum prediction and metabolite identification from tandem mass spectra","volume":"42","author":"Allen","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/18\/2\/73\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:44:28Z","timestamp":1760363068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/18\/2\/73"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,23]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["md18020073"],"URL":"https:\/\/doi.org\/10.3390\/md18020073","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,23]]}}}