Transcription factor-based biosensors: a molecular-guided approach for natural product engineering

Natural products and their derivatives offer a rich source of chemical and biological diversity; however, traditional engineering of their biosynthetic pathways to improve yields and access to unnatural derivatives requires a precise understanding of their enzymatic processes. High-throughput screening platforms based on allosteric transcription-factor based biosensors can be leveraged to overcome the screening bottleneck to enable searching through large libraries of pathway/strain variants. Herein, the development and application of engineered allosteric transcription factor-based biosensors is described that enable optimization of precursor availability, product titers, and downstream product tailoring for advancing the natural product bioeconomy. We discuss recent successes for tailoring biosensor design, including computationally-based approaches, and present our future outlook with the integration of cell-free technologies and de novo protein design for rapidly generating biosensor tools.