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Several of these compounds are highly active against multi\u2010drug resistant organisms. Despite the identification of the first members of this family almost 40 years ago, the genetic basis for the production of these molecules and the enzyme responsible for formation of the oxa bridge, remain unknown. Here, the 85 kb nargenicin biosynthetic gene cluster was identified from a human pathogenic <jats:italic>Nocardia arthritidis<\/jats:italic> isolate and this locus is solely responsible for nargenicin production. Further investigation of this locus revealed a putative iron\u2010\u03b1\u2010ketoglutarate\u2010dependent dioxygenase, which was found to be responsible for the formation of the ether bridge from the newly identified deoxygenated precursor, 8,13\u2010deoxynargenicin. Uncovering the nargenicin biosynthetic locus provides a molecular basis for the rational bioengineering of these interesting antibiotic macrolides.<\/jats:p>","DOI":"10.1002\/anie.201900290","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T23:15:31Z","timestamp":1548371731000},"page":"3996-4001","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Biosynthesis and Ether\u2010Bridge Formation in Nargenicin Macrolides"],"prefix":"10.1002","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1202-6614","authenticated-orcid":false,"given":"Sacha J.","family":"Pidot","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Herisse","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9324-8678","authenticated-orcid":false,"given":"Liam","family":"Sharkey","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liselle","family":"Atkin","sequence":"additional","affiliation":[{"name":"School of Chemistry The Bio21 Molecular Science and Biotechnology Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6046-610X","authenticated-orcid":false,"given":"Torsten","family":"Seemann","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"},{"name":"Microbioloigical Diagnostic Unit University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-1473","authenticated-orcid":false,"given":"Benjamin P.","family":"Howden","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"},{"name":"Microbioloigical Diagnostic Unit University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7297-1303","authenticated-orcid":false,"given":"Mark A.","family":"Rizzacasa","sequence":"additional","affiliation":[{"name":"School of Chemistry The Bio21 Molecular Science and Biotechnology Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0150-123X","authenticated-orcid":false,"given":"Timothy P.","family":"Stinear","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology at the Doherty Institute University of Melbourne  Melbourne VIC 3000 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,2,11]]},"reference":[{"key":"e_1_2_2_1_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7NP00019G"},{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.01.009"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.05496-11"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00283"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2015.08.015"},{"key":"e_1_2_2_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00532a036"},{"key":"e_1_2_2_7_1","unstructured":"\u201cNargenicin Compounds and Uses Thereof as Antibacterial Agents\u201d:K.Young D. 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