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Streptomyces spp. are a rich source for natural products with recognized industrial value, explaining the high interest to improve and streamline production in these microbes. Here, we studied the production of pamamycins, macrodiolide homologues with a high activity against multi-resistant pathogenic microbes, using recombinant S. albus J1074/R2. Talc particles (hydrous magnesium silicate, 3MgO·4SiO2 ·H2 O) of micrometer size added to submerged cultures of the recombinant strain tripled pamamycin production up to 50 mg L-1 . Furthermore, they strongly affected morphology, reduced the size of cell pellets, formed by the filamentous microbe during the process, up to six-fold, and shifted the pamamycin spectrum to larger derivatives. Integrated analysis of transcriptome and precursor (CoA thioester) supply of particle-enhanced and control cultures provided detailed insights into the underlying molecular changes. The microparticles affected the expression of 3341 genes (56%), revealing a global and fundamental impact on metabolism. Morphology-associated 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 1024-fold). Furthermore, the microparticles perturbed genes encoding for CoA-ester metabolism, which were mainly activated. The altered expression resulted in changes in the availability of intracellular CoA-esters, the building blocks of pamamycin. Notably, the ratio between methylmalonyl CoA and malonyl-CoA was increased four-fold. Both metabolites compete for incorporation into pamamycin so that the altered availability explained the pronounced preference for larger derivatives in the microparticle-enhanced process. The novel insights into the behavior of S. albus in response to talc appears of general relevance to further explore and upgrade the concept of microparticle enhanced cultivation, widely used for filamentous microbes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.