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As these antibiotics rely on a small set of chemical scaffolds and affect an even smaller number of biological targets, emergent AMR genes can spread through microbiomes to simultaneously inactivate multiple classes and generations of drugs. Long-overlooked for their perceived clinical limitations, antibacterial natural products with taxa-specific activities now present an underexplored source of design principles for precision antibiotics that can selectively eliminate individual microbes and limit community-wide incentives for AMR. Here, we present our re-investigation of one such taxa-specific antibacterial natural product, imacidin, a forgotten inhibitor of cell wall biosynthesis. We show that imacidin is the first natural product inhibitor of the peptidoglycan lipid II flippase MurJ, representing a larger, nascent class of taxa-specific cyclic lipopeptides that offer new leads for precision antibiotics.<\/jats:p>","DOI":"10.1101\/2025.10.02.680127","type":"posted-content","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T05:00:19Z","timestamp":1759554019000},"source":"Crossref","is-referenced-by-count":0,"title":["Cyclic lipopeptide natural products as taxa-specific antibacterial inhibitors of the lipid II flippase"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-0477","authenticated-orcid":false,"given":"Elizabeth B","family":"Barrois","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas H","family":"Costa-Martini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Thoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3756-7628","authenticated-orcid":false,"given":"Justin M","family":"Van Riper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Wochele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8820-8417","authenticated-orcid":false,"given":"Calla","family":"Olson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9364-1832","authenticated-orcid":false,"given":"Heike","family":"Br\u00f6tz-Oesterhelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1988-709X","authenticated-orcid":false,"given":"Chad W","family":"Johnston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101502101960000_2025.10.02.680127v3.1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.0c01214"},{"key":"2025101502101960000_2025.10.02.680127v3.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00791-6"},{"key":"2025101502101960000_2025.10.02.680127v3.3","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo7793"},{"key":"2025101502101960000_2025.10.02.680127v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07530-w"},{"key":"2025101502101960000_2025.10.02.680127v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.056"},{"key":"2025101502101960000_2025.10.02.680127v3.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00933-y"},{"key":"2025101502101960000_2025.10.02.680127v3.7","doi-asserted-by":"crossref","first-page":"102160","DOI":"10.1016\/j.cbpa.2022.102160","article-title":"Natural and engineered precision antibiotics in the context of resistance","volume":"69","year":"2022","journal-title":"Current Opinion in Chemical Biology"},{"key":"2025101502101960000_2025.10.02.680127v3.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2015.09.069"},{"key":"2025101502101960000_2025.10.02.680127v3.9","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41586-024-07502-0","article-title":"A Gram-negative-selective antibiotic that spares the gut microbiome","volume":"630","year":"2024","journal-title":"Nature"},{"key":"2025101502101960000_2025.10.02.680127v3.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06873-0"},{"key":"2025101502101960000_2025.10.02.680127v3.11","doi-asserted-by":"publisher","DOI":"10.1039\/c7np00019g"},{"key":"2025101502101960000_2025.10.02.680127v3.12","first-page":"2357","article-title":"[Structure of griselimycin, polypeptide antibiotic extracted from streptomyces cultures. 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