Abstract
Biomanufacturing offers a potentially sustainable alternative to deriving chemicals from fossil fuels. However, traditional biomanufacturing, which uses sugars as feedstocks, competes with food production and yields unfavourable land use changes, so more sustainable options are necessary. Cupriavidus necator is a chemolithoautotrophic bacterium capable of consuming carbon dioxide and hydrogen as sole carbon and energy sources, or formate as the source of both. This autotrophic metabolism potentially makes chemical production using C. necator sustainable and attractive for biomanufacturing. Additionally, C. necator natively fixes carbon in the form of poly-3-hydroxybutyrate, which can be processed to make biodegradable plastic. Recent progress in development of modelling and synthetic biology tools have made C. necator much more usable as a biomanufacturing chassis. However, these tools and applications are often limited by a lack of consideration for the unique physiology and metabolic features of C. necator. As such, further work is required to better understand the intricate mechanisms that allow it to prioritise generalization over specialization. In this review, progress toward physiology-informed engineering of C. necator across several dimensions is critically discussed, and recommendations for moving toward a physiological approach are presented. Arguments for metabolic specialization, more focus on autotrophic fermentation, C. necator-specific synthetic biology tools, and modelling that goes beyond constraints are presented based on analysis of existing literature.