{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T19:11:46Z","timestamp":1781291506180,"version":"3.54.1"},"reference-count":30,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:00:00Z","timestamp":1687219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National High Technology Research and Development Program of China","award":["2012AA022107"],"award-info":[{"award-number":["2012AA022107"]}]},{"name":"National High Technology Research and Development Program of China","award":["2001xg07"],"award-info":[{"award-number":["2001xg07"]}]},{"name":"National High Technology Research and Development Program of China","award":["LY19C010002"],"award-info":[{"award-number":["LY19C010002"]}]},{"name":"Scientific Research Foundation of Taizhou","award":["2012AA022107"],"award-info":[{"award-number":["2012AA022107"]}]},{"name":"Scientific Research Foundation of Taizhou","award":["2001xg07"],"award-info":[{"award-number":["2001xg07"]}]},{"name":"Scientific Research Foundation of Taizhou","award":["LY19C010002"],"award-info":[{"award-number":["LY19C010002"]}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["2012AA022107"],"award-info":[{"award-number":["2012AA022107"]}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["2001xg07"],"award-info":[{"award-number":["2001xg07"]}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["LY19C010002"],"award-info":[{"award-number":["LY19C010002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Avermectins (AVMs), a family of 16-membered macrocyclic macrolides produced by Streptomyces avermitilis, have been the most successful microbial natural antiparasitic agents in recent decades. Doramectin, an AVM derivative produced by S. avermitilis bkd\u2212 mutants through cyclohexanecarboxylic acid (CHC) feeding, was commercialized as a veterinary antiparasitic drug by Pfizer Inc. Our previous results show that the production of avermectin and actinorhodin was affected by several other polyketide biosynthetic gene clusters in S. avermitilis and Streptomyces coelicolor, respectively. Thus, here, we propose a rational strategy to improve doramectin production via the termination of competing polyketide biosynthetic pathways combined with the overexpression of CoA ligase, providing precursors for polyketide biosynthesis. fadD17, an annotated putative cyclohex-1-ene-1-carboxylate:CoA ligase-encoding gene, was proven to be involved in the biosynthesis of doramectin. By sequentially removing three PKS (polyketide synthase) gene clusters and overexpressing FadD17 in the strain DM203, the resulting strain DM223 produced approximately 723 mg\/L of doramectin in flasks, which was approximately 260% that of the original strain DM203 (approximately 280 mg\/L). To summarize, our work demonstrates a novel viable approach to engineer doramectin overproducers, which might contribute to the reduction in the cost of this valuable compound in the future.<\/jats:p>","DOI":"10.3390\/bioengineering10060739","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T02:26:56Z","timestamp":1687228016000},"page":"739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains"],"prefix":"10.3390","volume":"10","author":[{"given":"Fujun","family":"Dang","sequence":"first","affiliation":[{"name":"Key Laboratory of Synthetic Biology, The Center of Excellent Plant Molecular Sciences, The Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, The Center of Excellent Plant Molecular Sciences, The Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjun","family":"Qin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, The Center of Excellent Plant Molecular Sciences, The Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7068-4637","authenticated-orcid":false,"given":"Haiyang","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, The Center of Excellent Plant Molecular Sciences, The Chinese Academy of Sciences, Shanghai 200032, China"},{"name":"Institute of Biopharmaceuticals, Taizhou University, Taizhou 317000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1128\/AAC.15.3.361","article-title":"Avermectins, new family of potent anthelmintic agents: Producing organism and fermentation","volume":"15","author":"Burg","year":"1979","journal-title":"Antimicrob. 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