Metabolic engineering of antibiotic factories: new tools for antibiotic production in actinomycetes

Antibiotic discovery is a walk in the park

“…clone or synthesize de novo the gene cluster(s) involved in biosynthesis of a specific product, and to express it in a host organism (16,17). Although still not trivial, the improvement in the past decade in methods for assembling long genetic constructs in a different species host (17), yield optimization by pathway manipulation (18), and combinatorial biosynthesis (19) offer an exciting toolbox for accessing this molecular biodiversity.…”

Metabolic engineering with systems biology tools to optimize production of prokaryotic secondary metabolites

“…6 Recently, the discipline of metabolic engineering has increasingly been applied to the secondary metabolite studies to help boost commercial production of target molecules. 6,7 The general objective of metabolic engineering is to overproduce chemicals that are valuable to mankind from microbial or mammalian cells, and was rst coined in the eld of biochemical engineering. 8 By its denition, this discipline attempts to systematically understand and engineer a cell's metabolic network at a systems level.…”

“…Manipulation of BGCs, including inactivation or exchange of domains in polyketide synthase and non-ribosomal peptide synthetase, engineering of a domain active site and tailoring enzymes, and shuffling of modules, can all lead to the production of secondary metabolites with novel structures, and has been a classical topic in the secondary metabolite community. 6,15 With this background in mind, it has become important to view the production of secondary metabolites from the metabolic engineer's perspective. A motivation is that once a structurally novel molecule is sufficiently determined to have commercial value, its production titer and yield need to be enhanced in order to implement larger-scale experiments, including (pre)clinical trials, and ultimately industrial production (Fig.…”

“…Advanced synthetic biological tools greatly aid this process. 6,27 Finally, because general gene manipulation tools, such as knockout and overexpression of genes, have actively been applied to secondary metabolite-producing microorganisms as manifested in next section (Table S1 †), they no longer appear to be a limiting factor for host selection when producing secondary metabolites. In the same line, state-of-the-art synthetic biology tools mostly developed with model organisms (e.g., E. coli) are increasingly available to secondary metabolite producers.…”

Herboxidiene biosynthesis, production, and structural modifications: prospect for hybrids with related polyketide

“…Moreover, the system biological tools can help with the study of the connections between the primary and secondary metabolites of particular strains along with their regulation and signal transduction cascades (Hwang et al 2014). The current tools for advanced DNA synthesis and assembly of large fragments along with precise techniques for modulation at the gene level and high-throughput genome editing (Cobb et al 2014;Fernández-Martínez and Bibb 2014) have revolutionized the scope of metabolic engineering approaches for producing versatile secondary metabolites through host engineering (Pickens et al 2011;Siegl and Luzhetskyy 2012;Weber et al 2015). Regarding the feasibility of producing herboxidiene as a major metabolite with a yield surpassing ∼3 g/L (Jha et al 2014) or its successful modification using different substrate-flexible enzymes , S. chromofuscus presents itself as an amenable strain for established genetic engineering tools.…”