{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:08:30Z","timestamp":1789135710160,"version":"build-2803163510"},"reference-count":25,"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\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["202207940006"],"award-info":[{"award-number":["202207940006"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The development of antibacterials with unique mechanisms of action is key to addressing the threat posed by antibiotic resistance. Among the wide array of natural products that target bacterial cell wall biosynthesis, bacitracin A is the preeminent example of an antibiotic that functions by selectively targeting and sequestering the key bacterial phospholipid undecaprenyl pyrophosphate (C55PP). Historically, the bacitracins have been isolated from fermentations of Bacillus species. We recently discovered a series of structurally distinct bacitracin-like peptide antibiotics produced by members of the Paenibacillus genus, termed the paenitracins. Here, we report the total synthesis of paenitracin B (1), enabling definitive stereochemical validation of the previously proposed structure and delivering quantities of material suitable for more extensive antibacterial testing. The synthetic route developed was also applied to the preparation of paenitracin analogues, with some showing significantly enhanced antibacterial activity, particularly against VanA-type vancomycin-resistant Enterococcus faecium clinical isolates.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00198","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:01:19Z","timestamp":1787169679000},"page":"3002-3008","source":"Crossref","is-referenced-by-count":0,"title":["Total Synthesis\nof Paenitracin B and Analogues with\nEnhanced Antibacterial Activity"],"prefix":"10.1021","volume":"12","author":[{"given":"Yunhao","family":"Duan","sequence":"first","affiliation":[{"name":"Leiden University , , Sylviusweg 72 , , ,","place":["Leiden, The Netherlands, 2333 BE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Jongman","sequence":"additional","affiliation":[{"name":"Leiden University , , Sylviusweg 72 , , ,","place":["Leiden, The Netherlands, 2333 BE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9236-5821","authenticated-orcid":true,"given":"Vladyslav","family":"Lysenko","sequence":"additional","affiliation":[{"name":"Leiden University , , Sylviusweg 72 , , ,","place":["Leiden, The Netherlands, 2333 BE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9220","authenticated-orcid":true,"given":"Willem","family":"Jespers","sequence":"additional","affiliation":[{"name":"University of Groningen , , Antonius Deusinglaan 1 , ,","place":["Groningen, The Netherlands, 9713AV"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0341-1561","authenticated-orcid":true,"given":"Gilles P.","family":"van Wezel","sequence":"additional","affiliation":[{"name":"Leiden University , , Sylviusweg 72 , , ,","place":["Leiden, The Netherlands, 2333 BE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8530-1966","authenticated-orcid":true,"given":"Nataliia V.","family":"Machushynets","sequence":"additional","affiliation":[{"name":"Leiden University , , Sylviusweg 72 , , ,","place":["Leiden, The Netherlands, 2333 BE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-3006","authenticated-orcid":true,"given":"Nathaniel I.","family":"Martin","sequence":"additional","affiliation":[{"name":"Leiden University , , Sylviusweg 72 , , ,","place":["Leiden, The Netherlands, 2333 BE"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2026091109080825900_cit1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic\nAnalysis","volume":"399","year":"2022","journal-title":"Lancet"},{"issue":"4","key":"2026091109080825900_cit2","first-page":"277","article-title":"The Antibiotic\nResistance Crisis Part 1: Causes and Threats","volume":"40","author":"Ventola","year":"2015","journal-title":"P&T"},{"key":"2026091109080825900_cit3","volume-title":"Global\nantimicrobial resistance and use surveillance system (GLASS) report\n2022","year":"2022"},{"key":"2026091109080825900_cit4","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1080\/14787210.2017.1308251","article-title":"The Antibiotic Pipeline: Reviving\nResearch and Development\nand Speeding Drugs to Market","volume":"15","author":"Luepke","year":"2017","journal-title":"Expert Rev. Anti.\nInfect. Ther."},{"key":"2026091109080825900_cit5","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/med.21321","article-title":"Lipopeptides from Bacillus and Paenibacillus Spp.:\nA Gold Mine of Antibiotic Candidates","volume":"36","author":"Cochrane","year":"2016","journal-title":"Med. Res.\nRev."},{"key":"2026091109080825900_cit6","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1039\/C5NP00099H","article-title":"Recent Advances\nin Engineering Nonribosomal Peptide Assembly Lines","volume":"33","author":"Winn","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"2026091109080825900_cit7","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1039\/C8NP00031J","article-title":"Nonribosomal Antibacterial\nPeptides That Target Multidrug-Resistant Bacteria","volume":"36","author":"Liu","year":"2019","journal-title":"Nat. Prod. Rep."},{"issue":"6","key":"2026091109080825900_cit8","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1111\/j.1574-6976.2010.00221.x","article-title":"Natural Functions of\nLipopeptides from Bacillus and Pseudomonas: More than Surfactants and Antibiotics","volume":"34","author":"Raaijmakers","year":"2010","journal-title":"FEMS\nMicrobiol. Rev."},{"key":"2026091109080825900_cit9","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fmolb.2020.00087","article-title":"Repurposing Modular\nPolyketide Synthases and Nonribosomal Peptide Synthetases for Novel\nChemical Production","volume":"7","author":"Hwang","year":"2020","journal-title":"Front. Mol. Biosci."},{"issue":"3","key":"2026091109080825900_cit10","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1007\/s00253-018-9541-0","article-title":"Bacillus and Paenibacillus Secreted Polyketides and Peptides\nInvolved\nin Controlling Human and Plant Pathogens","volume":"103","author":"Olishevska","year":"2019","journal-title":"Appl.\nMicrobiol. Biotechnol."},{"issue":"9","key":"2026091109080825900_cit11","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1086\/429323","article-title":"Colistin:\nThe Revival of Polymyxins\nfor the Management of Multidrug-Resistant Gram-Negative Bacterial\nInfections","volume":"40","author":"Falagas","year":"2005","journal-title":"Clinical Infectious Diseases"},{"key":"2026091109080825900_cit12","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/S1473-3099(06)70580-1","article-title":"Colistin:\nThe Re-Emerging Antibiotic\nfor Multidrug-Resistant Gram-Negative Bacterial Infections","volume":"6","author":"Li","year":"2006","journal-title":"Lancet Infect. Dis."},{"issue":"10","key":"2026091109080825900_cit13","doi-asserted-by":"publisher","first-page":"a025288","DOI":"10.1101\/cshperspect.a025288","article-title":"Polymyxin: Alternative Mechanisms of Action and Resistance","volume":"6","author":"Trimble","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"2026091109080825900_cit14","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1073\/pnas.68.12.3223","article-title":"Mechanism\nof Action of Bacitracin: Complexation with\nMetal Ion and C55-Isoprenyl Pyrophosphate","volume":"68","author":"Stone","year":"1971","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"key":"2026091109080825900_cit15","doi-asserted-by":"publisher","first-page":"14207","DOI":"10.1073\/pnas.1308268110","article-title":"High-Resolution Crystal Structure\nReveals Molecular Details of Target Recognition by Bacitracin","volume":"110","author":"Economou","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"21","key":"2026091109080825900_cit16","doi-asserted-by":"publisher","first-page":"2925","DOI":"10.1128\/JB.00507-16","article-title":"Depletion\nof Undecaprenyl Pyrophosphate Phosphatases Disrupts Cell Envelope\nBiogenesis in Bacillus subtilis","volume":"198","author":"Zhao","year":"2016","journal-title":"J. Bacteriol."},{"issue":"29","key":"2026091109080825900_cit17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2315310121","article-title":"A Classic Antibiotic\nReimagined: Rationally Designed\nBacitracin Variants Exhibit Potent Activity against Vancomycin-Resistant\nPathogens","volume":"121","author":"Buijs","year":"2024","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"3","key":"2026091109080825900_cit18","doi-asserted-by":"publisher","first-page":"e01496","DOI":"10.1128\/msystems.01496-25","article-title":"Paenitracins, a Novel Family of Bacitracin-Type Nonribosomal\nPeptide Antibiotics Produced by Plant-Associated Paenibacillus Species","volume":"11","author":"Machushynets","year":"2026","journal-title":"mSystems"},{"key":"2026091109080825900_cit19","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and Community Curation of Mass Spectrometry\nData with Global Natural Products Social Molecular Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"2026091109080825900_cit20","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/s41592-020-0933-6","article-title":"Feature-Based Molecular Networking in the GNPS Analysis\nEnvironment","volume":"17","author":"Nothias","year":"2020","journal-title":"Nat. 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Agents Chemother."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00198","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/3002\/66883819\/acsinfecdis.6c00198.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/3002\/66883819\/acsinfecdis.6c00198.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:27:43Z","timestamp":1789133263000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/9\/3002\/5277002\/Total-Synthesis-of-Paenitracin-B-and-Analogues"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":25,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,19]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00198","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}