{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T03:43:19Z","timestamp":1781840599856,"version":"3.54.5"},"reference-count":33,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["835857"],"award-info":[{"award-number":["835857"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-093978-B-I00"],"award-info":[{"award-number":["RTI2018-093978-B-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Consejer\u00eda de Empleo, Industria y Turismo del Principado de Asturias","award":["FC-GRUPIN-IDI\/2018\/000120"],"award-info":[{"award-number":["FC-GRUPIN-IDI\/2018\/000120"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Streptomycetes are important biotechnological bacteria that produce several clinically bioactive compounds. They have a complex development, including hyphae differentiation and sporulation. Cytosolic copper is a well-known modulator of differentiation and secondary metabolism. The interruption of the Streptomyces coelicolor SCO2730 (copper chaperone, SCO2730::Tn5062 mutant) blocks SCO2730 and reduces SCO2731 (P-type ATPase copper export) expressions, decreasing copper export and increasing cytosolic copper. This mutation triggers the expression of 13 secondary metabolite clusters, including cryptic pathways, during the whole developmental cycle, skipping the vegetative, non-productive stage. As a proof of concept, here, we tested whether the knockdown of the SCO2730\/31 orthologue expression can enhance secondary metabolism in streptomycetes. We created a SCO2730\/31 consensus antisense mRNA from the sequences of seven key streptomycetes, which helped to increase the cytosolic copper in S. coelicolor, albeit to a lower level than in the SCO2730::Tn5062 mutant. This antisense mRNA affected the production of at least six secondary metabolites (CDA, 2-methylisoborneol, undecylprodigiosin, tetrahydroxynaphtalene, \u03b1-actinorhodin, \u03b5-actinorhodin) in the S. coelicolor, and five (phenanthroviridin, alkylresorcinol, chloramphenicol, pikromycin, jadomycin G) in the S. venezuelae; it also helped to alter the S. albus metabolome. The SCO2730\/31 consensus antisense mRNA designed here constitutes a tool for the knockdown of SCO2730\/31 expression and for the enhancement of Streptomyces\u2019 secondary metabolism.<\/jats:p>","DOI":"10.3390\/ijms221810143","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Modulation of SCO2730\/31 Copper Chaperone\/Transporter Orthologue Expression Enhances Secondary Metabolism in Streptomycetes"],"prefix":"10.3390","volume":"22","author":[{"given":"Nathaly","family":"Gonz\u00e1lez-Qui\u00f1\u00f3nez","sequence":"first","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5212-6199","authenticated-orcid":false,"given":"Ignacio","family":"Guti\u00e9rrez-Del-R\u00edo","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Garc\u00eda-Cancela","sequence":"additional","affiliation":[{"name":"Department of Physical and Analytical Chemistry, ISPA, Faculty of Chemistry, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2829-033X","authenticated-orcid":false,"given":"Sergio","family":"Alonso-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Yag\u00fce","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4560-3847","authenticated-orcid":false,"given":"\u00c1lvaro","family":"P\u00e9rez-Valero","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Montes-Bay\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Physical and Analytical Chemistry, ISPA, Faculty of Chemistry, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6680-6723","authenticated-orcid":false,"given":"Felipe","family":"Lomb\u00f3","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-8988","authenticated-orcid":false,"given":"\u00c1ngel","family":"Manteca","sequence":"additional","affiliation":[{"name":"\u00c1rea de Microbiolog\u00eda, Departamento de Biolog\u00eda Funcional, IUOPA, ISPA, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ja.2005.1","article-title":"Bioactive microbial metabolites","volume":"58","author":"Berdy","year":"2005","journal-title":"J. Antibiot."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hopwood, D.A. (2007). Streptomyces in Nature and Medicine: The Antibiotic Makers, Oxford University Press.","DOI":"10.1093\/oso\/9780195150667.001.0001"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrmicro1968","article-title":"Streptomyces morphogenetics: Dissecting differentiation in a filamentous bacterium","volume":"7","author":"Flardh","year":"2009","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/1574-6968.12128","article-title":"Pre-sporulation stages of Streptomyces differentiation: State-of-the-art and future perspectives","volume":"342","author":"Yague","year":"2013","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11274-019-2789-4","article-title":"The regulatory cascades of antibiotic production in Streptomyces","volume":"36","author":"Xia","year":"2020","journal-title":"World J. Microbiol. Biotechnol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/ja.2017.51","article-title":"Novel antibiotic screening methods to awaken silent or cryptic secondary metabolic pathways in actinomycetes","volume":"70","author":"Onaka","year":"2017","journal-title":"J. Antibiot."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41597-020-0395-9","article-title":"Thirty complete Streptomyces genome sequences for mining novel secondary metabolite biosynthetic gene clusters","volume":"7","author":"Lee","year":"2020","journal-title":"Sci. Data"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Manteca, A., and Yague, P. (2018). Streptomyces Differentiation in Liquid Cultures as a Trigger of Secondary Metabolism. Antibiotics, 7.","DOI":"10.3390\/antibiotics7020041"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaay5781","DOI":"10.1126\/sciadv.aay5781","article-title":"Antibiotic production in Streptomyces is organized by a division of labor through terminal genomic differentiation","volume":"6","author":"Zhang","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Nguyen, C.T., Dhakal, D., Pham, V.T.T., Nguyen, H.T., and Sohng, J.K. (2020). Recent Advances in Strategies for Activation and Discovery\/Characterization of Cryptic Biosynthetic Gene Clusters in Streptomyces. Microorganisms, 8.","DOI":"10.3390\/microorganisms8040616"},{"key":"ref_11","first-page":"565","article-title":"The ram-dependence of Streptomyces lividans differentiation is bypassed by copper","volume":"2","author":"Keijser","year":"2000","journal-title":"J. Mol. Microbiol. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"693","DOI":"10.7164\/antibiotics.50.693","article-title":"Stimulatory effect of copper on antibiotic production and morphological differentiation in Streptomyces tanashiensis","volume":"50","author":"Ueda","year":"1997","journal-title":"J. Antibiot."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4214","DOI":"10.1038\/s41598-019-40876-0","article-title":"Cytosolic copper is a major modulator of germination, development and secondary metabolism in Streptomyces coelicolor","volume":"9","author":"Rioseras","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/j.1751-7915.2011.00319.x","article-title":"Pleiotropic role of the Sco1\/SenC family copper chaperone in the physiology of Streptomyces","volume":"5","author":"Fujimoto","year":"2012","journal-title":"Microb. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11253","DOI":"10.1038\/s41598-019-46833-1","article-title":"Mechanism of CuO nano-particles on stimulating production of actinorhodin in Streptomyces coelicolor by transcriptional analysis","volume":"9","author":"Liu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1039\/b804465c","article-title":"Copper mining in Streptomyces: Enzymes, natural products and development","volume":"27","author":"Worrall","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1039\/C7MT00299H","article-title":"A cytosolic copper storage protein provides a second level of copper tolerance in Streptomyces lividans","volume":"10","author":"Straw","year":"2018","journal-title":"Metallomics"},{"key":"ref_18","unstructured":"Kieser, T. (2000). Practical Streptomyces Genetics, John Innes Foundation."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1126\/science.106.2757.417","article-title":"Chloromycetin, a New Antibiotic From a Soil Actinomycete","volume":"106","author":"Ehrlich","year":"1947","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ymben.2018.09.004","article-title":"Generation of a cluster-free Streptomyces albus chassis strains for improved heterologous expression of secondary metabolite clusters","volume":"49","author":"Myronovskyi","year":"2018","journal-title":"Metab. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12181","DOI":"10.1073\/pnas.1511027112","article-title":"Exploiting a precise design of universal synthetic modular regulatory elements to unlock the microbial natural products in Streptomyces","volume":"112","author":"Bai","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1039\/b817069j","article-title":"Genomic basis for natural product biosynthetic diversity in the actinomycetes","volume":"26","author":"Nett","year":"2009","journal-title":"Nat. Prod. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1099\/00221287-128-1-115","article-title":"Temperate Phages of Streptomyces venezuelae: Lysogeny and Host Specificity Shown by Phages SV1 and SV2","volume":"128","author":"Stuttard","year":"1982","journal-title":"Microbiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1139\/m92-125","article-title":"Sporulation of Streptomyces antibioticus ETHZ 7451 in submerged culture","volume":"38","author":"Novella","year":"1992","journal-title":"Can. J. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S1074-5521(02)00126-6","article-title":"The biosynthetic gene cluster for the antitumor rebeccamycin: Characterization and generation of indolocarbazole derivatives","volume":"9","author":"Sanchez","year":"2002","journal-title":"Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"21659","DOI":"10.1038\/srep21659","article-title":"Characterization of SCO4439, a D-alanyl-D-alanine carboxypeptidase involved in spore cell wall maturation, resistance, and germination in Streptomyces coelicolor","volume":"6","author":"Rioseras","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"128","DOI":"10.7164\/antibiotics.38.128","article-title":"Identification of a red pigment from Streptomyces coelicolor A3(2) as a mixture of prodigiosin derivatives","volume":"38","author":"Tsao","year":"1985","journal-title":"J. Antibiot."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1128\/jb.178.8.2238-2244.1996","article-title":"Production of actinorhodin-related \u201cblue pigments\u201d by Streptomyces coelicolor A3(2)","volume":"178","author":"Bystrykh","year":"1996","journal-title":"J. Bacteriol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1128\/AEM.02715-07","article-title":"Mycelium differentiation and antibiotic production in submerged cultures of Streptomyces coelicolor","volume":"74","author":"Manteca","year":"2008","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pluskal, T., Castillo, S., Villar-Briones, A., and Oresic, M. (2010). MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-395"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Pang, Z., Chong, J., Zhou, G., de Lima Morais, D.A., Chang, L., Barrette, M., Gauthier, C., Jacques, P.E., Li, S., and Xia, J. (2021). MetaboAnalyst 5.0: Narrowing the gap between raw spectra and functional insights. Nucleic Acids Res.","DOI":"10.1093\/nar\/gkab382"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/S1044-0305(99)00089-6","article-title":"Automation of a Fourier transform ion cyclotron resonance mass spectrometer for acquisition, analysis, and e-mailing of high-resolution exact-mass electrospray ionization mass spectral data","volume":"10","author":"Huang","year":"1999","journal-title":"J. Am. Soc. Mass Spectrom."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10143\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:35Z","timestamp":1760166155000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":33,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810143"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810143","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]}}}