Developing Streptomyces venezuelae as a cell factory for the production of small molecules used in drug discovery

Abstract

The heterologous expression of biosynthetic pathways is an indispensable tool for drug discovery and development from natural products. Streptomyces venezuelae is a promising heterologous host as it offers several attractive advantages, such as rapid growth rate, convenient genetic manipulation, and an abundant supply of common biosynthetic building blocks. In recent decades, several S. venezuelae mutant strains have been constructed and used to facilitate the synthesis and derivatization of diverse natural products. In this review article, we have provided a schematic look at these host strains, which were used to synthesize natural products from genetically engineered biosynthetic gene clusters.

Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products

“…E. coli is the most common, fast-growing, and easily manipulated host with comprehensive knowledge of the native metabolic networks; it has been used to produce a large number of metabolites and recombinant proteins (Kim et al, 2015b; Zhang et al, 2016b). The main limitation to using E. coli as a versatile heterologous host is the lack of specific biosynthetic machineries such as phosphopantetheinyl transferase (PPTase) and precursors such as methylmalonyl-CoA (Kim et al, 2015b), and the need for extensive genetic manipulations for actinomycete derived NPs (Zhang et al, 2016b).…”

“…E. coli is the most common, fast-growing, and easily manipulated host with comprehensive knowledge of the native metabolic networks; it has been used to produce a large number of metabolites and recombinant proteins (Kim et al, 2015b; Zhang et al, 2016b). The main limitation to using E. coli as a versatile heterologous host is the lack of specific biosynthetic machineries such as phosphopantetheinyl transferase (PPTase) and precursors such as methylmalonyl-CoA (Kim et al, 2015b), and the need for extensive genetic manipulations for actinomycete derived NPs (Zhang et al, 2016b). P. putida is a Gram-negative bacterium characterized by fast growth, well developed genetic tools, xenobiotic tolerance, a high NADPH generation rate and the presence of diverse enzymes; however, it has a low yield for polyketides and non-ribosomal peptides (NRPs) and the limited knowledge of its native metabolic networks largely restrict its applications (Zhang et al, 2016b).…”

“…Construction of a ‘clean’ host, in which endogenous BGCs have been removed, is generally preferred because more precursors, intermediates and energy can be directed towards the production of the heterologous metabolites (Kim et al, 2015b; Komatsu et al, 2010). Recent work on host engineering is also included.…”

Influence of glucose and stirring in the fermentation process in order to produce anti- Candida metabolites produced by Streptomyces sp.

“…Actinobacteria are Gram-positive filamentous bacteria group with high capacity to produce several secondary metabolites (Jørgensen et al, 2010;Karuppiah et al, 2013;Prakash et al, 2013;Kim, Yang, Yoon, 2015). They are usually isolated from soil consisting in about 30% of the microbial population (Goodfellow, Fiedler, 2010).…”

Development of an Unnatural Amino Acid Incorporation System in the Actinobacterial Natural Product Producer Streptomyces venezuelae ATCC 15439

“…S. venezuelae ATCC 15439 is among the most rapidly growing model Streptomyces hosts (doubling time of −1 h 10 ), grows in a dispersed manner in liquid culture, and can be genetically manipulated easily using either conjugation or protoplast transformation for introduction of plasmid DNA, making it a convenient host for synthetic biology applications. We used the E. coli-Streptomyces shuttle vector, pCMld 20 bearing SCP2* and ColElorigins of replication and an apramycin resistance marker, for construction of all plasmids expressing functional elements of the UAA incorporation system.…”