Microbial Strain Engineering for Biomanufacturing

In the evolving landscape of biomanufacturing, the demand for bio-based molecules such as secondary metabolites, vital for pharmaceutical, agricultural, and industrial applications, is rapidly growing. Microbial strain engineering stands at the forefront of this surge, offering innovative strain engineering services to enhance production. This article delves into some of the approaches that power the optimization of microorganisms for increased secondary metabolite output. Scientists at Isomerase have been successful in applying these techniques for our clients across a range of projects.

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How can microbial strain engineering improve secondary metabolite production?

Increasing titers of secondary metabolites is one of the primary goals of microbial strain engineering. This field has emerged as a pivotal force in biotechnology, driving advancements in the production of valuable secondary metabolites. Through the integration of metabolic engineering, synthetic biology, and genetic circuit optimization, this field enhances the genetic frameworks of microorganisms, leading to significant improvements in production efficiency and product specificity. While traditional methods remain valuable, modern strategies significantly amplify their effectiveness, establishing a new paradigm in strain optimization for biomanufacturing. Examples include inactivation of competing secondary metabolites (e.g. by cluster knockout), precursor supply improvement, adjustments to expression of parts of the pathway leading to accumulation of intermediates toxic to the cell, increased expression of parts of the biosynthesis pathway that are bottlenecks (e.g. a late stage methylation or hydroxylation), improvements to transport of the secondary metabolite out of the cell reducing intracellular accumulation, improving resistance of the strain to the product itself (e.g. by overexpressing a resistance marker).

Classical strain engineering

In this aspect of strain engineering, strains are subjected to mutagenic chemicals or radiation. Resulting strains accumulate random sequence variations. Some of these variations lead to an increase in target compound titers. By screening large numbers of treated colonies for productivity, higher producing isolates will eventually be found. The bottleneck of this method is usually the screen itself – the cost, speed and accuracy of this enable a more effective selection and higher chance of success. This approach can be labour-intensive, however, complementing these methods with targeted strain improvement can lead to superior production rates and efficiencies.

Metabolic Engineering: The Pathway to Enhanced Strains

Metabolic engineering is the cornerstone of microbial strain engineering. By redirecting and manipulating fluxes through chosen metabolic pathways, scientists can increase the yield of target metabolites. This strain optimization is achieved through the careful manipulation of enzymes and the genes encoding them, ensuring that the cellular machinery is optimized for production of the chosen product. More is not always best – enzymes have different rates and buildup of pathway intermediates is sometimes toxic to the producing cell, so different levels of expression of the key steps in the pathway are usually trialled to find an optimum. Scientists at Isomerase are experienced at applying both classical strain engineering and targeted metabolic engineering strategies in successful campaigns.

Synthetic Biology: The Architect of Microbial Factories 

Synthetic biology complements metabolic engineering by providing the tools to redesign organisms at a genetic level. The creation of synthetic genetic circuits and the removal of others allows for the fine-tuning of metabolic processes, thereby enhancing the production of desired secondary metabolites. Isomerase can engineer a wide range of microbes to increase the supply of precursors to a target metabolite, as well as knock out biosynthesis of alternative products competing for resources to arrive at a more robust and productive strain. The enzymes themselves can also be engineered, e.g. by Directed Evolution or Rational Engineering, improving the activity, stability or other properties of a key enzyme in a secondary metabolite pathway.

Genetic Circuit Optimization: Fine-Tuning for Peak Performance

The optimization of genetic circuits is critical for the efficient production of secondary metabolites. By employing advanced computational design models and bacterial genome editing technologies, researchers can develop specialised strains that serve as highly optimized biofactories, achieving unparalleled levels of efficiency and specificity.

Summary

The synergy between microbial strain engineering, metabolic engineering, synthetic biology, and genetic circuit optimization represents a powerful approach to revolutionizing the industrial-scale production of secondary metabolites. As your chosen innovation partner with a proven track record, Isomerase can provide strain engineering services to help achieve productivity and sustainability targets. Some of our successful case studies using strain engineering are detailed here.

If you are interested in learning more about our strain engineering services and how they can facilitate your project, contact our team for tailored support and solutions.

 

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