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Background  Heterologous expression of secondary metabolite gene clusters is used to achieve increased production of desired compounds, activate cryptic gene clusters, manipulate clusters from genetically unamenable strains, obtain natural products from uncultivable species, create new unnatural pathways, etc. Several  Streptomyces  species are genetically engineered for use as hosts for heterologous expression of gene clusters.  S. lividans  TK24 is one of the most studied and genetically tractable actinobacteria, which remain untapped. It was therefore important to generate  S. lividans  chassis strains with clean metabolic backgrounds.    Results  In this study, we generated a set of  S. lividans  chassis strains by deleting endogenous gene clusters and introducing additional φC31  attB  loci for site-specific integration of foreign DNA. In addition to the simplified metabolic background, the engineered  S. lividans  strains had better growth characteristics than the parental strain in liquid production medium. The utility of the developed strains was validated by expressing four secondary metabolite gene clusters responsible for the production of different classes of natural products. Engineered strains were found to be superior to the parental strain in production of heterologous natural products. Furthermore,  S. lividans -based strains were better producers of amino acid-based natural products than other tested common hosts. Expression of a  Streptomyces albus  subsp . chlorinus  NRRL B-24108 genomic library in the modified  S. lividans  ΔYA9 and  S. albus  Del14 strains resulted in the production of 7 potentially new compounds, only one of which was produced in both strains.    Conclusion  The constructed  S. lividans -based strains are a great complement to the panel of heterologous hosts for actinobacterial secondary metabolite gene expression. The expansion of the number of such engineered strains will contribute to an increased success rate in isolation of new natural products originating from the expression of genomic and metagenomic libraries, thus raising the chance to obtain novel biologically active compounds.

Engineering of Streptomyces lividans for heterologous expression of secondary metabolite gene clusters