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Herein, we describe a unique strategy for self\u2010resistance toward a macrolide antibiotic, A26771B (\n                    <jats:bold>1<\/jats:bold>\n                    ), identified by elucidating its biosynthetic pathway in the fungus Penicillium egyptiacum. A highly reducing polyketide synthase and a trans\u2010acting thioesterase generate the macrolide backbone, and a cytochrome P450 and an acyltransferase, respectively catalyze hydroxylation and succinylation to form the prodrug berkeleylactone\u2005E (\n                    <jats:bold>2<\/jats:bold>\n                    ). Then, extracellular oxidative activation by a secreted flavin\u2010dependent oxidase forms\n                    <jats:bold>1<\/jats:bold>\n                    , while intracellular reductive inactivation by a short\u2010chain reductase reforms\n                    <jats:bold>2<\/jats:bold>\n                    , forming a redox cycle. Our work illustrates a unique redox\u2010mediated resistance mechanism for fungal antibiotics and contributes to the understanding of antibiotic biosynthesis and resistance.\n                  <\/jats:p>","DOI":"10.1002\/anie.202015442","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T14:36:45Z","timestamp":1607956605000},"page":"6639-6645","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Self\u2010Resistance in the Biosynthesis of Fungal Macrolides Involving Cycles of Extracellular Oxidative Activation and Intracellular Reductive Inactivation"],"prefix":"10.1002","volume":"60","author":[{"given":"Yalong","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines NHC Key Laboratory of Biosynthesis of Natural Products CAMS Key Laboratory of Enzyme and Catalysis of Natural Drugs Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing 100050 P. 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