Synthetic Biology of secondary metabolite biosynthesis in actinomycetes: Engineering precursor supply as a way to optimize antibiotic production

Abstract

a b s t r a c tActinomycetes are a rich source for the synthesis of medically and technically useful natural products. The genes encoding the enzymes for their biosynthesis are normally organized in gene clusters, which include also the information for resistance (in the case of antibacterial compounds), regulation, and transport. This facilitates the manipulation of such pathways by molecular genetic techniques. Recent advances in DNA sequencing and analytical chemistry revealed that not only new strains isolated from yet unexplored habitats, but also already known strains possess a large potential for the synthesis of novel compounds. Synthetic Biology now offers a new perspective to exploit this potential further by generating novel pathways, and thereby novel products, by combining different biosynthetic steps originating from different bacteria. The supply of precursors, which are subsequently incorporated into the final product, is often already organized in a modular manner in nature and may directly be exploited for Synthetic Biology. Here we report examples for the synthesis of building blocks and possibilities to modify and optimize antibiotic biosynthesis, exemplary for the synthesis of the manipulation of the synthesis of the glycopeptide antibiotic balhimycin.

Antimicrobial Activity of Streptomyces Variabilis Strain-Vitumvb03 Isolated From Kanyakumari Marine Sediments

“…1). Considering the total number of isolates, the maximum number were isolated on actinobacterial isolation agar (4), followed by starch casein agar (2) and Kuster's agar (2). The isolates were identified using culture characteristics as mentioned in ISP manual.…”

“…Marine environment is already proven as a rich source for the production of bioactive compounds [1]. Among the bioactive compound producing organisms present in marine environments, Actinobacteria were found as the most potent group microorganisms producing a large variety of bioactive compounds such as antifungal, antibacterial, antioxidant, and antiviral agents [2]. Marine Actinobacteria are the most inventive producers of bioactive compounds.…”

Biogenesis of antibiotics—viewing its history and glimpses of the future

“…In an excellent recent review article, Wohlleben et al (2012) proposed that actinomycetes are a rich source for the synthesis of medically and technically useful natural products and that the genes encoding the enzymes for their biosynthesis are normally organized in gene clusters, which include also the information for resistance (in the case of antibacterial compounds), regulation, and transport. According to the authors, this facilitates the manipulation of such pathways by molecular genetic techniques.…”

Synthetic Biology of Antibiotic Production

“…In addition to a reduced background of endogenous secondary metabolites, an efficient chassis will also require an optimized primary metabolism for efficient precursor supply [72]. The importance of metabolic modeling for the optimization of secondary metabolite production hosts has been illustrated repeatedly, for example, in the generalized overproduction of pigmented antibiotics (actinorhodin and prodigiosins) in S. coelicolor upon the deletion of a phosphofructokinase isoform which, according to genome-scale modeling, was predicted to lead to an increased flux through the pentose phosphate pathway and toward the pigmented antibiotics [73].…”