{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:26:29Z","timestamp":1789921589410,"version":"4.0.1"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2008,5,1]],"date-time":"2008-05-01T00:00:00Z","timestamp":1209600000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Appl Environ Microbiol"],"published-print":{"date-parts":[[2008,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            We recently described a new method to activate antibiotic production in bacteria by introducing a mutation conferring resistance to a drug such as streptomycin, rifampin, paromomycin, or gentamicin. This method, however, enhanced antibiotic production by only up to an order of magnitude. Working with\n            <jats:italic>Streptomyces coelicolor<\/jats:italic>\n            A3(2), we established a method for the dramatic activation of antibiotic production by the sequential introduction of multiple drug resistance mutations. Septuple and octuple mutants, C7 and C8, thus obtained by screening for resistance to seven or eight drugs, produced huge amounts (1.63 g\/liter) of the polyketide antibiotic actinorhodin, 180-fold higher than the level produced by the wild type. This dramatic overproduction was due to the acquisition of mutant ribosomes, with aberrant protein and ppGpp synthesis activity, as demonstrated by in vitro protein synthesis assays and by the abolition of antibiotic overproduction with\n            <jats:italic>relA<\/jats:italic>\n            disruption. This new approach, called \u201cribosome engineering,\u201d requires less time, cost, and labor than other methods and may be widely utilized for bacterial strain improvement.\n          <\/jats:p>","DOI":"10.1128\/aem.02800-07","type":"journal-article","created":{"date-parts":[[2008,3,1]],"date-time":"2008-03-01T02:37:03Z","timestamp":1204339023000},"page":"2834-2840","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":128,"title":["Dramatic Activation of Antibiotic Production in\n            <i>Streptomyces coelicolor<\/i>\n            by Cumulative Drug Resistance Mutations"],"prefix":"10.1128","volume":"74","author":[{"given":"Guojun","family":"Wang","sequence":"first","affiliation":[{"name":"National Food Research Institute, Tsukuba, Ibaraki 305-8642, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Hosaka","sequence":"additional","affiliation":[{"name":"National Food Research Institute, Tsukuba, Ibaraki 305-8642, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozo","family":"Ochi","sequence":"additional","affiliation":[{"name":"National Food Research Institute, Tsukuba, Ibaraki 305-8642, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1369-5274(99)00005-3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00401-5"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03307.x"},{"key":"e_1_3_2_5_2","first-page":"1458","year":"1996","unstructured":"Cashel, M., D. 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