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Here, we studied the production of pamamycins, macrodiolide homologs with a high activity against multiresistant pathogenic microbes, using recombinant <jats:italic>Streptomyces albus<\/jats:italic> J1074\/R2. Talc particles (hydrous magnesium silicate, 3MgO\u00b74SiO<jats:sub>2<\/jats:sub>\u00b7H<jats:sub>2<\/jats:sub>O) of micrometer size, added to submerged cultures of the recombinant strain, tripled pamamycin production up to 50\u2009mg\/L. Furthermore, they strongly affected morphology, reduced the size of cell pellets formed by the filamentous microbe during the process up to sixfold, and shifted the pamamycin spectrum to larger derivatives. Integrated analysis of transcriptome and precursor (CoA thioester) supply of particle\u2010enhanced and control cultures provided detailed insights into the underlying molecular changes. The microparticles affected the expression of 3,341 genes (56% of all genes), revealing a global and fundamental impact on metabolism. Morphology\u2010associated genes, encoding major regulators such as SsgA, RelA, EshA, Factor C, as well as chaplins and rodlins, were found massively upregulated, indicating that the particles caused a substantially accelerated morphogenesis. In line, the pamamycin cluster was strongly upregulated (up to 1,024\u2010fold). Furthermore, the microparticles perturbed genes encoding for CoA\u2010ester metabolism, which were mainly activated. The altered expression resulted in changes in the availability of intracellular CoA\u2010esters, the building blocks of pamamycin. Notably, the ratio between methylmalonyl CoA and malonyl\u2010CoA was increased fourfold. Both metabolites compete for incorporation into pamamycin so that the altered availability explained the pronounced preference for larger derivatives in the microparticle\u2010enhanced process. The novel insights into the behavior of <jats:italic>S. albus<\/jats:italic> in response to talc appears of general relevance to further explore and upgrade the concept of microparticle enhanced cultivation, widely used for filamentous microbes.<\/jats:p>","DOI":"10.1002\/bit.27537","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T00:49:49Z","timestamp":1598575789000},"page":"3858-3875","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Microparticles globally\u00a0reprogram <i>Streptomyces albus<\/i> toward accelerated morphogenesis, streamlined carbon core metabolism, and enhanced production of the antituberculosis polyketide pamamycin"],"prefix":"10.1002","volume":"117","author":[{"given":"Martin","family":"Kuhl","sequence":"first","affiliation":[{"name":"Institute of Systems Biotechnology Saarland University Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Gl\u00e4ser","sequence":"additional","affiliation":[{"name":"Institute of Systems Biotechnology Saarland University Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriy","family":"Rebets","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmaceutical Biotechnology Saarland University Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"R\u00fcckert","sequence":"additional","affiliation":[{"name":"Center for Biotechnology Bielefeld University Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namrata","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Genedata GmbH Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hartsch","sequence":"additional","affiliation":[{"name":"Genedata GmbH Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9052-1998","authenticated-orcid":false,"given":"J\u00f6rn","family":"Kalinowski","sequence":"additional","affiliation":[{"name":"Center for Biotechnology Bielefeld University Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6497-0047","authenticated-orcid":false,"given":"Andriy","family":"Luzhetskyy","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmaceutical Biotechnology Saarland University Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7952-985X","authenticated-orcid":false,"given":"Christoph","family":"Wittmann","sequence":"additional","affiliation":[{"name":"Institute of Systems Biotechnology Saarland University Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12934-020-1277-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1096"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11274-016-2148-7"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.260110607"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2017.12.001"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hlca.19720550126"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01942-09"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.260370507"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20130214"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2012.08070.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M600367-MCP200"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-145-9-2245"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6308762"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.179.18.5854-5861.1997"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/B801658P"},{"key":"e_1_2_10_17_1","first-page":"89","article-title":"Morphological and physiological differentiation in Streptomyces","volume":"16","author":"Chater K. 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