Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation

Abstract

Titer improvement is a constant requirement in the fermentation industry. The traditional method of "random mutation and screening" has been very effective despite the considerable amount of time and resources it demands. Rational metabolic engineering, with the use of recombinant DNA technology, provides a novel, alternative strategy for titer improvement that complements the empirical method used in industry. Manipulation of the specific regulatory systems that govern secondary metabolite production is an important aspect of metabolic engineering that can efficiently improve fermentation titers. In this review, we use examples from Streptomyces secondary metabolism, the most prolific source of clinically used drugs, to demonstrate the power and utility of exploiting natural regulatory networks, in particular pathway-specific regulators, for titer improvement. Efforts to improve the titers of fredericamycin, C-1027, platensimycin, and platencin in our lab are highlighted.

Fig. 1

Strategies to increase secondary metabolite titers by manipulating pathway regulations

Fig. 2

Structures of C-1027, fredericamycins (FDMs), neocarzinostatin (NCS), platensimycin, and platencin, whose titers have been improved by engineering their pathway specific regulators in either the native producers, heterologous hosts, or both