Challenges in the Application of Synthetic Biology Toward Synthesis of Commodity Products by Cyanobacteria via "Direct Conversion"

Cyanobacterial direct conversion of CO₂ to several commodity chemicals has been recognized as a potential contributor to support the much-needed sustainable development of human societies. However, the feasibility of this "green conversion" hinders on our ability to overcome the hurdles presented by the natural evolvability of microbes. The latter may result in the genetic instability of engineered cyanobacterial strains leading to impaired productivity. This challenge is general to any "cell factory" approach in which the cells grow for multiple generations, and based on several studies carried out in different microbial hosts, we could identify that three distinct strategies have been proposed to tackle it. These are (1) to reduce microbial evolvability by decreasing the native mutation rate, (2) to align product formation with cell growth/fitness, and, paradoxically, (3) to efficiently reallocate cellular resources to product formation by uncoupling it from growth. The implementation of either of these strategies requires an advanced synthetic biology toolkit. Here, we review the existing methods available for cyanobacteria and identify areas of focus in which specific developments are still needed. Furthermore, we discuss how potentially stabilizing strategies may be used in combination leading to further increases of productivity while ensuring the stability of the cyanobacterial-based direct conversion process.