Mathematical modeling of ABE fermentation: Effects of gene knockouts and enhancements on solvent production

Numerous challenges still face the economical production of biobutanol from acetone-butanol-ethanol (ABE) fermentation in clostridium species, mainly due to low titers and product inhibition. Gene manipulation in clostridium has been one of the routes used to enhance butanol production, targeting several genes of the acidogenic and solventogenic pathways. Specifically, the histidine kinase knockout has shown to play a crucial role in enhancing butanol production in clostridium species. In this work we present a comprehensive kinetic model of ABE fermentation of two clostridium strains, the ATCC 55025 and ATCC 824 subjected to various combinations of gene knockouts and overexpressions. The ATCC 55025 and ATCC 824 models include the mechanistic effects of histidine kinase knockout on sporulation and solventogenesis, alone and in combination with other acidogenic knockouts and solventogenic overexpressions. A second model of ATCC 824 features the combination of BEKW strain with several solventogenic over-expressions. The model parameters were estimated by fitting the model to experimental data from the literature. The models were further analyzed by performing global sensitivity analysis and generating confidence intervals using a non-parametric bootstrap method. The three models were found to be in good agreement with the published experimental data and provide insight into the complex metabolic pathway interactions of the clostridium fermentation.