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Polyketide belongs to a family of abundant natural products typically produced by the filamentous soil bacteria Streptomyces. Similar to the biosynthesis of most secondary metabolites produced in the Streptomyces species, polyketide compounds are synthesized through tight regulatory networks in the cell, and thus extremely low levels of polyketides are typically observed in wild-type strains. Although many Streptomyces polyketides and their derivatives have potential to be used as clinically important pharmaceutical drugs, traditional strain improvement strategies such as random recursive mutagenesis have long been practiced with little understanding of the molecular basis underlying enhanced polyketide production. Recently, identifying, understanding, and applying a novel polyketide regulatory system identified from various Omics approaches, has become an important tool for rational Streptomyces strain improvement. In this paper, DNA microarray-driven reverse engineering efforts for improving titers of polyketides are briefly summarized, primarily focusing on our recent results of identification and application of novel global regulatory genes such as wblA, SCO1712, and SCO5426 in Streptomyces species. Sequential targeted gene manipulation involved in polyketide biosynthetic reguation synergistically provided an efficient and rational strategy for Streptomyces strain improvement. Moreover, the engineered regulation-optimized Streptomyces mutant strain was further used as a surrogate host for heterologous expression of polyketide pathway.

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