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We previously reported that a stilbene dimer from Photorhabdus gammaproteobacteria exhibits strong activity relative to its monomer against the multidrug-resistant Gram-positive pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis. Here, we show that related dietary plant stilbene-derived dimers also have activity against these pathogens, and MRSA is unable to develop substantial resistance even after daily nonlethal exposure to the lead compound for a duration of three months. Through a systematic deduction process, we established the mode of action of the lead dimer, which targets the bacterial cell wall. Genome sequencing of modest resistance mutants, mass spectrometry analysis of cell wall precursors, and exogenous lipid II chemical complementation studies support the target as being lipid II itself or lipid II trafficking processes. Given the broad distribution of stilbenes in plants, including dietary plants, we anticipate that our mode of action studies here could be more broadly applicable to multipartite host\u2013bacterium\u2013plant interactions.<\/jats:p>","DOI":"10.1021\/acs.biochem.0c00213","type":"journal-article","created":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T11:40:07Z","timestamp":1589542807000},"page":"1966-1971","source":"Crossref","is-referenced-by-count":13,"title":["Dimeric Stilbene Antibiotics Target the Bacterial\nCell Wall in Drug-Resistant Gram-Positive Pathogens"],"prefix":"10.1021","volume":"59","author":[{"given":"Tyler\nN.","family":"Goddard","sequence":"first","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]},{"name":"Yale University , , , ,","place":["West Haven, Connecticut, United States, 06516"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4380-4805","authenticated-orcid":true,"given":"Jaymin","family":"Patel","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["West Haven, Connecticut, United States, 06516"]},{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2986-3833","authenticated-orcid":true,"given":"Hyun Bong","family":"Park","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]},{"name":"Yale University , , , ,","place":["West Haven, Connecticut, United States, 06516"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7583-1242","authenticated-orcid":true,"given":"Jason M.","family":"Crawford","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]},{"name":"Yale University , , , ,","place":["West Haven, Connecticut, United States, 06516"]},{"name":"Yale University School of Medicine , , , ,","place":["New Haven, Connecticut, United States, 06536"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"issue":"3","key":"2026081416091543000_cit1","first-page":"226","article-title":"On the Antibacterial\nAction of Cultures of a Penicillium, with Special Reference to Their\nUse in the Isolation of B. influenzae","volume":"10","author":"Fleming","year":"1929","journal-title":"Br. J.\nExp. Pathol."},{"issue":"3","key":"2026081416091543000_cit2","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1093\/jac\/dkv484","article-title":"Antibiotics:\nfrom prehistory to the present day","volume":"71","author":"Gould","year":"2016","journal-title":"J. Antimicrob.\nChemother."},{"issue":"1","key":"2026081416091543000_cit3","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/nrmicro3380","article-title":"Molecular\nmechanisms of antibiotic resistance","volume":"13","author":"Blair","year":"2015","journal-title":"Nat. Rev.\nMicrobiol."},{"key":"2026081416091543000_cit4","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00539","article-title":"Emerging\nStrategies to Combat ESKAPE Pathogens in the Era of Antimicrobial\nResistance: A Review","author":"Mulani","year":"2019","journal-title":"Front. Microbiol."},{"issue":"2","key":"2026081416091543000_cit5","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.drudis.2015.01.009","article-title":"An analysis of FDA-approved\ndrugs: natural products and their derivatives","volume":"21","author":"Patridge","year":"2016","journal-title":"Drug Discovery Today"},{"issue":"3","key":"2026081416091543000_cit6","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1021\/np068054v","article-title":"Natural products\nas sources of new drugs over the last\n25 years","volume":"70","author":"Newman","year":"2007","journal-title":"J. Nat. Prod."},{"issue":"3","key":"2026081416091543000_cit7","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products\nas Sources of New Drugs from 1981\nto 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"issue":"7","key":"2026081416091543000_cit8","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1039\/b905960a","article-title":"Natural\nstilbenes: an overview","volume":"26","author":"Shen","year":"2009","journal-title":"Nat. Prod. Rep."},{"issue":"15","key":"2026081416091543000_cit9","doi-asserted-by":"publisher","first-page":"4108","DOI":"10.1002\/anie.201210116","article-title":"Formation of 1,3-Cyclohexanediones\nand Resorcinols\nCatalyzed by a Widely Occuring Ketosynthase","volume":"52","author":"Fuchs","year":"2013","journal-title":"Angew. Chem., Int. Ed."},{"issue":"2","key":"2026081416091543000_cit10","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s10295-013-1356-5","article-title":"Merging\nchemical ecology with bacterial genome mining\nfor secondary metabolite discovery","volume":"41","author":"Vizcaino","year":"2014","journal-title":"J. Ind.\nMicrobiol. Biotechnol."},{"issue":"4","key":"2026081416091543000_cit11","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1039\/C7NP00054E","article-title":"Chemical language\nand warfare of bacterial natural\nproducts in bacteria-nematode-insect interactions","volume":"35","author":"Shi","year":"2018","journal-title":"Nat. Prod. Rep."},{"issue":"3","key":"2026081416091543000_cit12","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1007\/BF00987707","article-title":"Antibiotics in Microbial\nEcology - Isolation and Structure Assignment of Several New Anti-Bacterial\nCompounds from the Insect-Symbiotic Bacteria Xenorhabdus Spp","volume":"7","author":"Paul","year":"1981","journal-title":"J. Chem. 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Chem.\nBiol."},{"issue":"1","key":"2026081416091543000_cit29","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/MRM.0b013e3283587727","article-title":"beta-Lactams:\nchemical structure,\nmode of action and mechanisms of resistance. Rev. Med","volume":"24","author":"Fernandes","year":"2013","journal-title":"Microbiol."},{"issue":"8","key":"2026081416091543000_cit30","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1016\/j.jnutbio.2013.05.001","article-title":"Benefits of polyphenols on gut microbiota and implications\nin human health","volume":"24","author":"Cardona","year":"2013","journal-title":"J. Nutr. Biochem."},{"issue":"2","key":"2026081416091543000_cit31","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3390\/nu8020078","article-title":"The Reciprocal Interactions between\nPolyphenols and Gut Microbiota and Effects on Bioaccessibility","volume":"8","author":"Ozdal","year":"2016","journal-title":"Nutrients"}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.0c00213","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/59\/21\/1966\/9473734\/bi0c00213.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/59\/21\/1966\/9473734\/bi0c00213.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T20:24:19Z","timestamp":1786739059000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/59\/21\/1966\/880384\/Dimeric-Stilbene-Antibiotics-Target-the-Bacterial"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,15]]},"references-count":31,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,5,15]]},"published-print":{"date-parts":[[2020,6,2]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.0c00213","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,15]]}}}