{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:07:49Z","timestamp":1793275669922,"version":"4.5.0"},"reference-count":56,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f?r Forschung, Technologie und Raumfahrt","doi-asserted-by":"publisher","award":["01DK24009"],"award-info":[{"award-number":["01DK24009"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["468811723; LU 1524\/14-1"],"award-info":[{"award-number":["468811723; LU 1524\/14-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The global rise of antibiotic resistance poses a public health challenge, emphasizing the urgent need for novel antibiotics featuring unique chemical scaffolds and mechanisms of action. Here, we report the discovery and characterization of darumycins, guanidine-containing pentacyclic sesterterpene antibiotics that exhibit potent activity against high-priority Gram-positive pathogens and mycobacteria. The darumycin biosynthetic gene cluster was identified through genome mining in the Actinobacterium Micromonospora rubida and heterologously expressed in Streptomyces chassis strains. Gene cluster engineering facilitated the discovery of novel darumycin derivatives, thereby expanding the chemical diversity within the sesterterpene class of natural products and revealing nuanced variations in their bioactivity. Targeted gene deletions, along with LC\u2013MS and NMR analyses, enabled us to propose a darumycin biosynthetic pathway, further complemented by in vitro biochemical characterization of two O-methyltransferase tailoring enzymes, DarM and DarG. The high-resolution crystal structure of DarM in complex with SAH provided valuable insights into the enzymatic mechanism and revealed a distinct architecture compared to other methyltransferases acting on terpene scaffolds.<\/jats:p>","DOI":"10.1021\/jacsau.6c00499","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T15:01:55Z","timestamp":1787151715000},"page":"4944-4955","source":"Crossref","is-referenced-by-count":3,"title":["Discovery and Biosynthetic\nCharacterization of Darumycins\nExpand the Chemical Space of Sesterterpene Antibiotics"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7272-5306","authenticated-orcid":true,"given":"Dmytro","family":"Bratiichuk","sequence":"first","affiliation":[{"name":"Saarland University , , Bld. C2.3 , ,","place":["Saarbru\u0308cken, Germany, 66123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Kolling","sequence":"additional","affiliation":[{"name":"Institute of Food Chemistry, Leibniz University Hannover , ,","place":["Hannover, Germany, 30167"]},{"name":"Saarland University , , ,","place":["Saarbru\u0308cken, Germany, 66123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma","family":"Redzic","sequence":"additional","affiliation":[{"name":"Saarland University , , Bld. C2.3 , ,","place":["Saarbru\u0308cken, Germany, 66123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Stierhof","sequence":"additional","affiliation":[{"name":"Saarland University , , Bld. C2.3 , ,","place":["Saarbru\u0308cken, Germany, 66123"]},{"name":"Saarland University , , ,","place":["Saarbru\u0308cken, Germany, 66123"]},{"name":"Infection und Pandemic Research (IIP) , , ,","place":["Mu\u0308nchen, Germany, 80799"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6485-8317","authenticated-orcid":true,"given":"Franziska","family":"Fries","sequence":"additional","affiliation":[{"name":"Saarland University , , ,","place":["Saarbru\u0308cken, Germany, 66123"]},{"name":"German Center for Infection Research (DZIF) , Partner Site Hannover-Braunschweig , ,","place":["Braunschweig, Germany, 38124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Zapp","sequence":"additional","affiliation":[{"name":"Saarland University , , Bld. C2.3 , ,","place":["Saarbru\u0308cken, Germany, 66123"]},{"name":"Saarland University , , ,","place":["Saarbru\u0308cken, Germany, 66123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1042-5665","authenticated-orcid":true,"given":"Rolf","family":"Mu\u0308ller","sequence":"additional","affiliation":[{"name":"Saarland University , , ,","place":["Saarbru\u0308cken, Germany, 66123"]},{"name":"German Center for Infection Research (DZIF) , Partner Site Hannover-Braunschweig , ,","place":["Braunschweig, Germany, 38124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksym","family":"Myronovskyi","sequence":"additional","affiliation":[{"name":"Saarland University , , Bld. C2.3 , ,","place":["Saarbru\u0308cken, Germany, 66123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesko","family":"Koehnke","sequence":"additional","affiliation":[{"name":"Institute of Food Chemistry, Leibniz University Hannover , ,","place":["Hannover, Germany, 30167"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6497-0047","authenticated-orcid":true,"given":"Andriy","family":"Luzhetskyy","sequence":"additional","affiliation":[{"name":"Saarland University , , Bld. C2.3 , ,","place":["Saarbru\u0308cken, Germany, 66123"]},{"name":"Saarland University , , ,","place":["Saarbru\u0308cken, Germany, 66123"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"issue":"2\u20133","key":"2026092808082667500_cit1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/s10295-015-1723-5","article-title":"Natural Product Discovery: Past, Present, and Future","volume":"43","author":"Katz","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."},{"issue":"19","key":"2026092808082667500_cit2","doi-asserted-by":"publisher","first-page":"12415","DOI":"10.1021\/acs.chemrev.7b00283","article-title":"Natural\nProducts as Platforms To\nOvercome Antibiotic Resistance","volume":"117","author":"Rossiter","year":"2017","journal-title":"Chem. Rev."},{"key":"2026092808082667500_cit3","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.mib.2019.10.008","article-title":"Antibiotics:\nPast, Present and Future","volume":"51","author":"Hutchings","year":"2019","journal-title":"Curr. Opin. Microbiol."},{"key":"2026092808082667500_cit4","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.3389\/fmicb.2016.02149","article-title":"Molecules\nto Ecosystems: Actinomycete Natural Products in situ","volume":"7","author":"Behie","year":"2017","journal-title":"Front. Microbiol."},{"issue":"3","key":"2026092808082667500_cit5","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00393-22","article-title":"Harnessing\nRare Actinomycete Interactions and Intrinsic Antimicrobial Resistance\nEnables Discovery of an Unusual Metabolic Inhibitor","volume":"13","author":"McClung","year":"2022","journal-title":"mBio"},{"issue":"6","key":"2026092808082667500_cit6","doi-asserted-by":"publisher","first-page":"a027029","DOI":"10.1101\/cshperspect.a027029","article-title":"Aminoglycosides:\nAn Overview","volume":"6","author":"Krause","year":"2016","journal-title":"Cold Spring Harbor Perspect. Med."},{"key":"2026092808082667500_cit7","doi-asserted-by":"publisher","first-page":"113293","DOI":"10.1016\/j.ejmech.2021.113293","article-title":"Antimicrobial\nDrugs Bearing Guanidine\nMoieties: A Review","volume":"216","author":"Kim","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"2026092808082667500_cit8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4172\/2157-7064.1000e126","article-title":"Two Functional\nGuanidine Groups Are Responsible for the Biological Activity of Streptomycin\nand Functionally Equivalent Molecules","volume":"05","author":"Moussa","year":"2014","journal-title":"J. Chromatogr.\nSep. Tech."},{"issue":"10","key":"2026092808082667500_cit9","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1517\/13543770903216675","article-title":"Biological Activities\nof Guanidine Compounds","volume":"19","author":"Saczewski","year":"2009","journal-title":"Expert Opin. Ther. Pat."},{"key":"2026092808082667500_cit10","doi-asserted-by":"publisher","first-page":"324","DOI":"10.3390\/md15100324","article-title":"Recent\nAdvances in the Isolation,\nSynthesis and Biological Activity of Marine","volume":"15","author":"Liu","year":"2017","journal-title":"Mar. 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Fungi"},{"key":"2026092808082667500_cit14","doi-asserted-by":"publisher","first-page":"kuaf024","DOI":"10.1093\/jimb\/kuaf024","article-title":"Biosynthesis of Guanidine-Containing\nNatural Products\nin Cyanobacteria","volume":"52","author":"Zhang","year":"2025","journal-title":"J. Ind. Microbiol. Biotechnol."},{"issue":"3","key":"2026092808082667500_cit15","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1039\/D0NP00051E","article-title":"The Chemistry and Biology of Guanidine Secondary Metabolites","volume":"38","author":"Berlinck","year":"2021","journal-title":"Nat. Prod. Rep."},{"issue":"1","key":"2026092808082667500_cit16","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1039\/D0NP00027B","article-title":"New Developments\nin RiPP Discovery, Enzymology and Engineering","volume":"38","author":"Montalba\u0301n-Lo\u0301pez","year":"2021","journal-title":"Nat. Prod. 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Prod."},{"issue":"7","key":"2026092808082667500_cit23","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1039\/D0NP00070A","article-title":"Sesterterpenoids: Chemistry, Biology, and Biosynthesis","volume":"38","author":"Li","year":"2021","journal-title":"Nat. Prod. Rep."},{"issue":"3","key":"2026092808082667500_cit24","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1039\/d4np00041b","article-title":"Sesterterpenoids:\nSources, Structural Diversity, Biological Activity, and Data Management","volume":"42","author":"Iobbi","year":"2025","journal-title":"Nat. Prod. Rep."},{"issue":"12","key":"2026092808082667500_cit25","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1039\/D1NP00021G","article-title":"The Untapped Potential of Plant Sesterterpenoids: Chemistry,\nBiological Activities and Biosynthesis","volume":"38","author":"Guo","year":"2021","journal-title":"Nat.\nProd. Rep."},{"issue":"10","key":"2026092808082667500_cit26","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.3390\/jof8101080","article-title":"Research Progress on\nFungal Sesterterpenoids Biosynthesis","volume":"8","author":"Zhang","year":"2022","journal-title":"J. Fungi"},{"issue":"1","key":"2026092808082667500_cit27","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.apsb.2023.08.025","article-title":"Genomics-Driven Derivatization of the Bioactive Fungal\nSesterterpenoid Variecolin: Creation of an Unnatural Analogue with\nImproved Anticancer Properties","volume":"14","author":"Yan","year":"2024","journal-title":"Acta Pharm.\nSin. B"},{"key":"2026092808082667500_cit28","doi-asserted-by":"publisher","first-page":"987","DOI":"10.3390\/md10050987","article-title":"Cytotoxic\nSesterterpenoids from a\nSponge Hippospongia sp","volume":"10","author":"Chang","year":"2012","journal-title":"Mar. 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Biol."},{"issue":"45","key":"2026092808082667500_cit32","doi-asserted-by":"publisher","first-page":"19961","DOI":"10.1002\/anie.202010084","article-title":"The Biosynthetic Gene Cluster for Sestermobaraenes-Discovery\nof a Geranylfarnesyl Diphosphate Synthase and a Multiproduct Sesterterpene\nSynthase from Streptomyces mobaraensis","volume":"59","author":"Hou","year":"2020","journal-title":"Angew. Chem. Int. Ed."},{"issue":"16","key":"2026092808082667500_cit33","doi-asserted-by":"publisher","first-page":"11140","DOI":"10.1021\/acs.joc.1c00262","article-title":"Marinoterpins A\u2013C: Rare Linear\nMerosesterterpenoids from Marine-Derived Actinomycete Bacteria of\nthe Family Streptomycetaceae","volume":"86","author":"Kim","year":"2021","journal-title":"J. Org. Chem."},{"issue":"48","key":"2026092808082667500_cit34","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202313789","article-title":"Subrutilane\nA Hexacyclic Sesterterpene from Streptomyces subrutilus","volume":"62","author":"Gu","year":"2023","journal-title":"Angew. Chem., Int. Ed."},{"issue":"3","key":"2026092808082667500_cit35","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1021\/ci300467b","article-title":"In silico Comparison of Antimycobacterial Natural Products\nwith Known Antituberculosis Drugs","volume":"53","author":"Espinoza-Moraga","year":"2013","journal-title":"J. Chem.\nInf. Model."},{"key":"2026092808082667500_cit36","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/j.biopha.2017.04.030","article-title":"Antibacterial, Antifungal and Antimycobacterial\nCompounds from Cyanobacteria","volume":"90","author":"Swain","year":"2017","journal-title":"Biomed. Pharmacother."},{"issue":"22","key":"2026092808082667500_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202422270","article-title":"Gromomycins:\nAn Unprecedented Class of Triterpene Antibiotics\nProduced by a Novel Biosynthetic Pathway","volume":"137","author":"Tistechok","year":"2025","journal-title":"Angew.\nChem., Int. Ed."},{"issue":"3","key":"2026092808082667500_cit38","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1021\/acschembio.5c00821","article-title":"Genome Mining-Driven\nIsolation of New Gromomycins and Insights into Their Mode of Action","volume":"21","author":"Bratiichuk","year":"2026","journal-title":"ACS Chem. 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Eng."},{"issue":"1","key":"2026092808082667500_cit41","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s12934-020-1277-8","article-title":"Engineering\nof Streptomyces lividans for Heterologous Expression\nof Secondary Metabolite Gene Clusters","volume":"19","author":"Ahmed","year":"2020","journal-title":"Microb.\nCell Fact."},{"issue":"1","key":"2026092808082667500_cit42","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.108","article-title":"Protein Sequence Analysis\nUsing the MPI Bioinformatics Toolkit","volume":"72","author":"Gabler","year":"2020","journal-title":"Curr.\nProtoc Bioinformatics"},{"issue":"24","key":"2026092808082667500_cit43","doi-asserted-by":"publisher","first-page":"6142","DOI":"10.1021\/ol302782u","article-title":"Carboxyl Formation\nfrom Methyl via Triple Hydroxylations by XiaM in Xiamycin A Biosynthesis","volume":"14","author":"Zhang","year":"2012","journal-title":"Org. Lett."},{"issue":"1","key":"2026092808082667500_cit44","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1021\/acs.jnatprod.5b00634","article-title":"Antiviral\nIndolosesquiterpenoid Xiamycins C\u2013E from a Halophilic Actinomycete","volume":"79","author":"Kim","year":"2016","journal-title":"J. Nat. Prod."},{"issue":"8","key":"2026092808082667500_cit45","doi-asserted-by":"publisher","first-page":"3403","DOI":"10.1007\/s00253-020-10481-7","article-title":"Artificial Control of the Multistep\nOxidation Reactions Catalyzed\nby the Cytochrome P450 Enzyme RosC","volume":"104","author":"Iizaka","year":"2020","journal-title":"Appl. Microbiol.\nBiotechnol."},{"issue":"18","key":"2026092808082667500_cit46","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202200212","article-title":"Methyltransferases: Functions and Applications","volume":"23","author":"Abdelraheem","year":"2022","journal-title":"Chembiochem"},{"issue":"6","key":"2026092808082667500_cit47","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/S0968-0004(03)00090-2","article-title":"Many Paths to Methyltransfer: a Chronicle\nof Convergence","volume":"28","author":"Schubert","year":"2003","journal-title":"Trends Biochem. Sci."},{"issue":"6","key":"2026092808082667500_cit48","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/S0959-440X(02)00391-3","article-title":"SAM (dependent)\nI AM: the S-adenosylmethionine-dependent\nmethyltransferase fold","volume":"12","author":"Martin","year":"2002","journal-title":"Curr. Opin. Struct.\nBiol."},{"issue":"4","key":"2026092808082667500_cit49","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1021\/acschembio.5b00905","article-title":"Sequential Inactivation\nof Gliotoxin by the S-Methyltransferase\nTmtA","volume":"11","author":"Duell","year":"2016","journal-title":"ACS Chem. Bio."},{"key":"2026092808082667500_cit50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1142\/9789812813077_0001","article-title":"Structure and Evolution of Adomet-Dependent\nMethyltransferases. In S-Adenosylmethionine-Dependent Methyltransferases","author":"Fauman","year":"1999","journal-title":"Sci. World"},{"issue":"6","key":"2026092808082667500_cit51","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1039\/b919371p","article-title":"Enzymes\nthat Catalyse SN2 Reaction Mechanisms","volume":"27","author":"O\u2019Hagan","year":"2010","journal-title":"Nat.\nProd. 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