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Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant\n                    <jats:italic>Enterococcus<\/jats:italic>\n                    (VRE), methicillin-resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (MRSA), as well as vancomycin-resistant\n                    <jats:italic>S. aureus<\/jats:italic>\n                    (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding\n                    <jats:sc>d<\/jats:sc>\n                    -Ala-\n                    <jats:sc>d<\/jats:sc>\n                    -Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2208737120","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T15:10:27Z","timestamp":1680534627000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2133-2533","authenticated-orcid":false,"given":"Alessandra","family":"Ottonello","sequence":"first","affiliation":[{"name":"La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, 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Biodiscovery Institute and School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1920-5036","authenticated-orcid":false,"given":"Paul","family":"Williams","sequence":"additional","affiliation":[{"name":"National Biofilms Innovation Centre, Biodiscovery Institute and School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4346-182X","authenticated-orcid":false,"given":"Jani R.","family":"Bolla","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Oxford, Oxford OX1 3RB, U.K."},{"name":"The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, 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