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Background   Streptomyces chattanoogensis  L10 is the industrial producer of natamycin and has been proved a highly efficient host for diverse natural products. It has an enormous potential to be developed as a versatile cell factory for production of heterologous secondary metabolites. Here we developed a genome-reduced industrial  Streptomyces chassis  by rational ‘design-build-test’ pipeline.    Results  To identify candidate large non-essential genomic regions accurately and design large deletion rationally, we performed genome analyses of  S. chattanoogensis  L10 by multiple computational approaches, optimized Cre/ loxP  recombination system for high-efficient large deletion and constructed a series of universal suicide plasmids for rapid  loxP  or  loxP  mutant sites inserting into genome. Subsequently, two genome-streamlined mutants, designated  S. chattanoogensis  L320 and L321, were rationally constructed by depletion of 1.3 Mb and 0.7 Mb non-essential genomic regions, respectively. Furthermore, several biological performances like growth cycle, secondary metabolite profile, hyphae morphological engineering, intracellular energy (ATP) and reducing power (NADPH/NADP + ) levels, transformation efficiency, genetic stability, productivity of heterologous proteins and secondary metabolite were systematically evaluated. Finally, our results revealed that L321 could serve as an efficient  chassis  for the production of polyketides.    Conclusions  Here we developed the combined strategy of multiple computational approaches and site-specific recombination system to rationally construct genome-reduced  Streptomyces  hosts with high efficiency. Moreover, a genome-reduced industrial  Streptomyces chassis   S. chattanoogensis  L321 was rationally constructed by the strategy, and the  chassis  exhibited several emergent and excellent performances for heterologous expression of secondary metabolite. The strategy could be widely applied in other  Streptomyces  to generate miscellaneous and versatile  chassis  with minimized genome. These  chassis  can not only serve as cell factories for high-efficient production of valuable polyketides, but also will provide great support for the upgrade of microbial pharmaceutical industry and drug discovery.    Electronic supplementary material  The online version of this article (10.1186/s12934-019-1055-7) contains supplementary material, which is available to authorized users.

Rational construction of genome-reduced and high-efficient industrial Streptomyces chassis based on multiple comparative genomic approaches