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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,16]]},"abstract":"<jats:p>\n                    Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C\n                    <jats:sub>55<\/jats:sub>\n                    PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C\n                    <jats:sub>55<\/jats:sub>\n                    PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin\u2013C\n                    <jats:sub>55<\/jats:sub>\n                    PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure\u2013activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C\n                    <jats:sub>55<\/jats:sub>\n                    PP. The structure\u2013activity insights thus obtained serve to inform the design of C\n                    <jats:sub>55<\/jats:sub>\n                    PP-targeting antibiotics, a key and underexploited antibacterial strategy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2315310121","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T13:50:29Z","timestamp":1720705829000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["A classic antibiotic reimagined: Rationally designed bacitracin variants exhibit potent activity against vancomycin-resistant pathogens"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-4951","authenticated-orcid":false,"given":"Ned P.","family":"Buijs","sequence":"first","affiliation":[{"name":"Biological Chemistry Group, Institute of Biology, Leiden University, Leiden 2333 BE, The 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