Engineering microbial hosts for production of bacterial natural products

Abstract

Microbial fermentation provides as an attractive alternative to chemical synthesis for the production of structurally complex natural products. In most cases, however, production titers are low and need to be improved for compound characterization and/or commercial production. Owing to advances in functional genomics and genetic engineering technologies, microbial hosts can be engineered to overproduce a desired natural product, greatly accelerating the traditionally time-consuming strain improvement process. This review covers recent developments and challenges in the engineering of native and heterologous microbial hosts for production of bacterial natural products, focusing on the genetic tools and strategies for strain improvement. Special emphasis is placed on bioactive secondary metabolites from actinomycetes. The considerations for the choice of host systems will also be discussed in this review.

Breaking the silence: new strategies for discovering novel natural products

“…Previously we developed a plug-and-play refactoring workflow based on DNA assembly and successfully activated a silent polycyclic tetramate macrolactam BGC [50,51]. For more details about this strategy, readers are referred to recent reviews [52,53]. …”

Using natural products for drug discovery: the impact of the genomics era

“…Here we highlight the major strategies to activate BGC expression with a focus on natural product discovery. Readers are referred to recent reviews for details on the metabolic, pathway and genome engineering approaches in native and heterologous host systems for secondary metabolite production [33, 34, 35]. …”

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

“…[40] To circumvent the limitations encountered when using the standard restriction-and ligation-based cloning for genetic manipulation, the E. coli-derived λ Red system was applied for faster and more efficient gene disruption, in-frame deletion, gene replacement, and refactoring of entire gene clusters in Streptomyces strains. [41] To aid genetic engineering effort even further in streptomycetes, an alternative to this classical method was reported using the S. cerevisiae I-SceI homing endonuclease for DNA double strand break (DSB)-based genome editing.…”

“…First, if the native host is reluctant toward any genome engineering efforts, heterologous expression might prove a helpful alternative. [40,57] Strains such as S. albus, S. avermitilis, S. coelicolor, and Streptomyces lividans are readily amenable to cloning and expression, and therefore, their use as heterologous hosts circumvents native host limitations. [58] Also, the construction of genome-minimized hosts, which have had one or more BGCs removed from their genomes, might improve titers of a given product by avoiding the use of common precursors for other secondary metabolites.…”