Dynamic optimization of a fed-batch nosiheptide reactor

Abstract

Nosiheptide is a sulfur-containing peptide antibiotic, showing exceptional activity against critical pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) with livestock applications that can be synthesized via fed-batch fermentation. A simplified mechanistic fed-batch fermentation model for nosiheptide production considers temperature- and pH-dependence of biomass growth, substrate consumption, nosiheptide production and oxygen mass transfer into the broth. Herein, we perform dynamic simulation over a broad range of possible feeding policies to understand and visualize the region of attainable reactor performances. We then formulate a dynamic optimization problem for maximization of nosiheptide production for different constraints of batch duration and operability limits. A direct method for dynamic optimization (simultaneous strategy) is performed in each case to compute the optimal control trajectories. Orthogonal polynomials on finite elements are used to approximate the control and state trajectories allowing the continuous problem to be converted to a nonlinear program (NLP). The resultant large-scale NLP is solved using IPOPT. Optimal operation requires feedrate to be manipulated in such a way that the inhibitory mechanism of the substrate can be avoided, with significant nosiheptide yield improvement realized.