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The relationship between different biosynthetic gene clusters (BGCs) and the MIL BGC remains unclear, which hinders the precise metabolic engineering of <jats:italic>S. bingchenggensis<\/jats:italic> for titer improvement. To address this issue, this study discovered the regulatory function of a previously unidentified regulator KelR on a type\u2010II polyketide BGC, MIL BGC, and two other BGCs, and caused titer improvement. First, a type II polyketide synthase (PKS) gene cluster <jats:italic>kel<\/jats:italic> with a bidirectional effect on MIL biosynthesis was found using transcriptome analysis. A <jats:italic>Streptomyces<\/jats:italic> antibiotic regulatory protein (SARP) family regulator KelR from the <jats:italic>kel<\/jats:italic> cluster was then characterized as an activator of several BGCs including <jats:italic>mil<\/jats:italic> and <jats:italic>kel<\/jats:italic> clusters. Metabolic competition between <jats:italic>mil<\/jats:italic> and <jats:italic>kel<\/jats:italic> clusters at the late fermentation stage was confirmed. Finally, KelR and those BGCs were manipulated in <jats:italic>S. bingchenggensis<\/jats:italic>, which led to a 71.7% titer improvement of MIL A3\/A4 to 4058.2\u2009\u00b1\u200971.0\u2009mg\/L. This study deciphered the regulatory function of a previously unidentified regulatory protein KelR on several BGCs including <jats:italic>mil<\/jats:italic> in <jats:italic>S. bingchenggensis<\/jats:italic> and provided an example of coordinating metabolic competition and coregulation for titer improvement of secondary metabolites.<\/jats:p>","DOI":"10.1002\/bit.28044","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T07:43:22Z","timestamp":1643269402000},"page":"1252-1263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co\u2010activation controlled by <i>Streptomyces<\/i> antibiotic regulatory protein family regulator in <i>Streptomyces bingchenggensis<\/i>"],"prefix":"10.1002","volume":"119","author":[{"given":"Haiyan","family":"Wang","sequence":"first","affiliation":[{"name":"State 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