{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:12:00Z","timestamp":1790809920764,"version":"4.1.0"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32270095"],"award-info":[{"award-number":["32270095"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011258","name":"State Key Laboratory of Microbial Metabolism","doi-asserted-by":"publisher","award":["MMLKF24-08"],"award-info":[{"award-number":["MMLKF24-08"]}],"id":[{"id":"10.13039\/501100011258","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFA0905400"],"award-info":[{"award-number":["2019YFA0905400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Metabolic Engineering"],"published-print":{"date-parts":[[2026,7]]},"DOI":"10.1016\/j.ymben.2026.04.006","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:34:40Z","timestamp":1776443680000},"page":"290-301","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Multifaceted metabolic engineering of Streptomyces hygroscopicus for milbemycins overproduction"],"prefix":"10.1016","volume":"96","author":[{"given":"Jiafeng","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guosong","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delin","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinhua","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ymben.2026.04.006_bib1","doi-asserted-by":"crossref","first-page":"6002","DOI":"10.1038\/ncomms7002","article-title":"Sequencing of first-strand cDNA library reveals full-length transcriptomes","volume":"6","author":"Agarwal","year":"2015","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ymben.2026.04.006_bib2","doi-asserted-by":"crossref","first-page":"272","DOI":"10.7164\/antibiotics.49.272","article-title":"Further novel milbemycin antibiotics from Streptomyces sp. E225. Fermentation, isolation and structure elucidation","volume":"49","author":"Baker","year":"1996","journal-title":"J. Antibiot."},{"key":"10.1016\/j.ymben.2026.04.006_bib3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12934-016-0619-z","article-title":"Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074","volume":"16","author":"Bilyk","year":"2017","journal-title":"Microb. Cell Fact."},{"key":"10.1016\/j.ymben.2026.04.006_bib4","doi-asserted-by":"crossref","first-page":"11383","DOI":"10.1093\/nar\/gku828","article-title":"Chromosome position effects on gene expression in Escherichia coli K-12","volume":"42","author":"Bryant","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ymben.2026.04.006_bib5","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12934-019-1055-7","article-title":"Rational construction of genome-reduced and high-efficient industrial Streptomyces chassis based on multiple comparative genomic approaches","volume":"18","author":"Bu","year":"2019","journal-title":"Microb. Cell Fact."},{"key":"10.1016\/j.ymben.2026.04.006_bib6","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1007\/s10295-019-02196-0","article-title":"Improved production of clavulanic acid by reverse engineering and overexpression of the regulatory genes in an industrial Streptomyces clavuligerus strain","volume":"46","author":"Cho","year":"2019","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib7","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nrmicro3238","article-title":"Coordination of microbial metabolism","volume":"12","author":"Chubukov","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"10.1016\/j.ymben.2026.04.006_bib8","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2222045120","article-title":"Dissection of 3D chromosome organization in Streptomyces coelicolor A3(2) leads to biosynthetic gene cluster overexpression","volume":"120","author":"Deng","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.ymben.2026.04.006_bib9","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1186\/s12864-017-3900-6","article-title":"Increasing quality, throughput and speed of sample preparation for strand-specific messenger RNA sequencing","volume":"18","author":"Haile","year":"2017","journal-title":"BMC Genom."},{"key":"10.1016\/j.ymben.2026.04.006_bib10","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1007\/s00253-022-11847-9","article-title":"Crossregulation of rapamycin and elaiophylin biosynthesis by RapH in Streptomyces rapamycinicus","volume":"106","author":"He","year":"2022","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib11","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1128\/AEM.02262-09","article-title":"Cloning of separate meilingmycin biosynthesis gene clusters by use of acyltransferase-ketoreductase didomain PCR amplification","volume":"76","author":"He","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"10.1016\/j.ymben.2026.04.006_bib12","doi-asserted-by":"crossref","first-page":"5358","DOI":"10.1021\/acs.jafc.3c09101","article-title":"Low-toxicity and high-efficiency Streptomyces genome editing tool based on the miniature type V-F CRISPR\/Cas nuclease AsCas12f1","volume":"72","author":"Hua","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"10.1016\/j.ymben.2026.04.006_bib13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10295-013-1327-x","article-title":"Genome mining of the Streptomyces avermitilis genome and development of genome-minimized hosts for heterologous expression of biosynthetic gene clusters","volume":"41","author":"Ikeda","year":"2014","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib14","doi-asserted-by":"crossref","first-page":"4803","DOI":"10.1038\/s41598-017-05073-x","article-title":"GdmRIII, a TetR family transcriptional regulator, controls geldanamycin and elaiophylin biosynthesis in Streptomyces autolyticus CGMCC0516","volume":"7","author":"Jiang","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.ymben.2026.04.006_bib15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12934-017-0626-8","article-title":"Engineered biosynthesis of milbemycins in the avermectin high-producing strain Streptomyces avermitilis","volume":"16","author":"Kim","year":"2017","journal-title":"Microb. Cell Fact."},{"key":"10.1016\/j.ymben.2026.04.006_bib16","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1073\/pnas.0914833107","article-title":"Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism","volume":"107","author":"Komatsu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.ymben.2026.04.006_bib17","article-title":"Streptomyces as a versatile host platform for heterologous production of microbial natural products","author":"Lasch","year":"2025","journal-title":"Nat. Prod. Rep."},{"key":"10.1016\/j.ymben.2026.04.006_bib18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ymben.2018.12.001","article-title":"aMSGE: advanced multiplex site-specific genome engineering with orthogonal modular recombinases in actinomycetes","volume":"52","author":"Li","year":"2019","journal-title":"Metab. Eng."},{"key":"10.1016\/j.ymben.2026.04.006_bib19","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ymben.2015.02.001","article-title":"A stepwise increase in pristinamycin II biosynthesis by Streptomyces pristinaespiralis through combinatorial metabolic engineering","volume":"29","author":"Li","year":"2015","journal-title":"Metab. Eng."},{"key":"10.1016\/j.ymben.2026.04.006_bib20","doi-asserted-by":"crossref","first-page":"12845","DOI":"10.1021\/acs.jafc.5c00613","article-title":"Enhancement of acarbose production in Actinoplanes sp. QQ-12 via multiple engineering strategies","volume":"73","author":"Liu","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"10.1016\/j.ymben.2026.04.006_bib21","article-title":"Balancing cell growth and product synthesis for efficient microbial cell factories","volume":"12","author":"Liu","year":"2025","journal-title":"Adv. Sci. (Weinh.)"},{"key":"10.1016\/j.ymben.2026.04.006_bib22","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1007\/s00253-021-11164-7","article-title":"Engineering of primary metabolic pathways for titer improvement of milbemycins in Streptomyces bingchenggensis","volume":"105","author":"Liu","year":"2021","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib23","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"10.1016\/j.ymben.2026.04.006_bib24","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ymben.2003.12.001","article-title":"Reverse engineering of industrial pharmaceutical-producing actinomycete strains using DNA microarrays","volume":"6","author":"Lum","year":"2004","journal-title":"Metab. Eng."},{"key":"10.1016\/j.ymben.2026.04.006_bib25","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jbiotec.2016.05.038","article-title":"An influence of the copy number of biosynthetic gene clusters on the production level of antibiotics in a heterologous host","volume":"232","author":"Manderscheid","year":"2016","journal-title":"J. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib26","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1111\/1744-7917.12829","article-title":"Carboxylesterase genes in nitenpyram-resistant brown planthoppers, Nilaparvata lugens","volume":"28","author":"Mao","year":"2021","journal-title":"Insect Sci."},{"key":"10.1016\/j.ymben.2026.04.006_bib27","doi-asserted-by":"crossref","first-page":"12215","DOI":"10.1073\/pnas.211433198","article-title":"Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites","volume":"98","author":"Omura","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.ymben.2026.04.006_bib28","doi-asserted-by":"crossref","first-page":"8188","DOI":"10.1093\/nar\/gkaa602","article-title":"Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in Streptomyces","volume":"48","author":"Tian","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ymben.2026.04.006_bib29","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1128\/AEM.65.9.3793-3799.1999","article-title":"Development and characterization of a gene expression reporter system for Clostridium acetobutylicum ATCC 824","volume":"65","author":"Tummala","year":"1999","journal-title":"Appl. Environ. Microbiol."},{"key":"10.1016\/j.ymben.2026.04.006_bib30","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1002\/bit.28044","article-title":"Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co\u2010activation controlled by Streptomyces antibiotic regulatory protein family regulator in Streptomyces bingchenggensis","volume":"119","author":"Wang","year":"2022","journal-title":"Biotechnol. Bioeng."},{"key":"10.1016\/j.ymben.2026.04.006_bib31","doi-asserted-by":"crossref","first-page":"9703","DOI":"10.1007\/s00253-014-5970-6","article-title":"Combined application of plasma mutagenesis and gene engineering leads to 5-oxomilbemycins A3\/A4 as main components from Streptomyces bingchenggensis","volume":"98","author":"Wang","year":"2014","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib32","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ymben.2025.11.015","article-title":"Engineering amino acid-derived malonyl-CoA pathways to boost polyketide production in Yarrowia lipolytica","volume":"94","author":"Wang","year":"2025","journal-title":"Metab. Eng."},{"key":"10.1016\/j.ymben.2026.04.006_bib33","doi-asserted-by":"crossref","first-page":"29717","DOI":"10.1021\/acs.jafc.5c08276","article-title":"Enhancement of spinosyn production by integrating a static and dynamic CRISPRi-mediated metabolic switch in Saccharopolyspora spinosa","volume":"73","author":"Wang","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"10.1016\/j.ymben.2026.04.006_bib34","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s11274-009-9986-5","article-title":"Improvement of milbemycin-producing Streptomyces bingchenggensis by rational screening of ultraviolet- and chemically induced mutants","volume":"25","author":"Wang","year":"2009","journal-title":"World J. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib35","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1139\/gen-2013-0098","article-title":"Characterization and analysis of an industrial strain of Streptomyces bingchenggensis by genome sequencing and gene microarray","volume":"56","author":"Wang","year":"2013","journal-title":"Genome"},{"key":"10.1016\/j.ymben.2026.04.006_bib36","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1016\/j.tibtech.2025.06.003","article-title":"Tunable dynamic engineering of cellular NAD boosts the production of antibiotics in actinomycetes","volume":"43","author":"Wu","year":"2025","journal-title":"Trends Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib37","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/ja.2007.78","article-title":"Further new milbemycin antibiotics from Streptomyces bingchenggensis: fermentation, isolation, structural elucidation and biological activities","volume":"60","author":"Xiang","year":"2007","journal-title":"J. Antibiot."},{"key":"10.1016\/j.ymben.2026.04.006_bib38","doi-asserted-by":"crossref","first-page":"5849","DOI":"10.1007\/s00203-021-02575-1","article-title":"Recent advances in the research of milbemycin biosynthesis and regulation as well as strategies for strain improvement","volume":"203","author":"Yan","year":"2021","journal-title":"Arch. Microbiol."},{"key":"10.1016\/j.ymben.2026.04.006_bib39","doi-asserted-by":"crossref","DOI":"10.1038\/s41587-025-02762-1","article-title":"Scalable secondary metabolite production in Streptomyces using a plug-and-play system","author":"Yang","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib40","doi-asserted-by":"crossref","DOI":"10.1111\/1751-7915.14470","article-title":"Enhancement of acyl\u2010 CoA precursor supply for increased avermectin B1a production by engineering meilingmycin polyketide synthase and key primary metabolic pathway genes","volume":"17","author":"Yang","year":"2024","journal-title":"Microb. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib41","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1002\/npp2.18","article-title":"Recent advances of natural product pesticide milbemycins from Streptomyces","volume":"1","author":"Yang","year":"2024","journal-title":"New Plant Protection"},{"key":"10.1016\/j.ymben.2026.04.006_bib42","doi-asserted-by":"crossref","first-page":"5701","DOI":"10.1007\/s00253-023-12661-7","article-title":"High-titer production of staurosporine by heterologous expression and process optimization","volume":"107","author":"Zhang","year":"2023","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib43","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s11427-019-1559-y","article-title":"Multiplex genome editing using a dCas9-cytidine deaminase fusion in Streptomyces","volume":"63","author":"Zhao","year":"2020","journal-title":"Sci. China Life Sci."},{"key":"10.1016\/j.ymben.2026.04.006_bib44","doi-asserted-by":"crossref","first-page":"5069","DOI":"10.1007\/s00253-013-4893-y","article-title":"A simplified diphenylamine colorimetric method for growth quantification","volume":"97","author":"Zhao","year":"2013","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"10.1016\/j.ymben.2026.04.006_bib45","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.synbio.2025.03.008","article-title":"iCASRED, a scarless DNA editing tool in E. coli for high-efficiency engineering of natural product biosynthetic gene clusters","volume":"10","author":"Zheng","year":"2025","journal-title":"Synth Syst Biotechnol"},{"key":"10.1016\/j.ymben.2026.04.006_bib46","doi-asserted-by":"crossref","first-page":"11250","DOI":"10.1073\/pnas.1006085107","article-title":"Reverse biological engineering of hrdB to enhance the production of avermectins in an industrial strain of Streptomyces avermitilis","volume":"107","author":"Zhuo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Metabolic Engineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1096717626000595?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1096717626000595?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T16:07:51Z","timestamp":1780934871000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1096717626000595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":46,"alternative-id":["S1096717626000595"],"URL":"https:\/\/doi.org\/10.1016\/j.ymben.2026.04.006","relation":{},"ISSN":["1096-7176"],"issn-type":[{"value":"1096-7176","type":"print"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Multifaceted metabolic engineering of Streptomyces hygroscopicus for milbemycins overproduction","name":"articletitle","label":"Article Title"},{"value":"Metabolic Engineering","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ymben.2026.04.006","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 International Metabolic Engineering Society. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}]}}