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.
Highlights
Antibiotics are essential pharmaceutical products in modern society [1], whose syntheses either require complex multistep chemical routes [2,3] or make use of enzymatic pathways [4] to obtain their complex molecular structures
Simultaneous strategies require the ordinary differential equations (ODEs) system to be discretized on the time horizon to produce a large-scale nonlinear programming (NLP) problem requiring no further integration of the differential algebraic equation (DAE) system, generally using orthogonal collocation techniques
The fed-batch production of nosiheptide is considered to circumvent mass transfer inhibition at at excessive substrate concentrations in the fermentation broth, where the reactor is only partially excessive substrate concentrations in the fermentation broth, where the reactor is only partially filled filled initially and substrate supplemented over time
Summary
Antibiotics are essential pharmaceutical products in modern society [1], whose syntheses either require complex multistep chemical routes [2,3] or make use of enzymatic pathways [4] to obtain their complex molecular structures. Designing efficient antibiotic manufacturing processes is imperative. Nosiheptide (Figure 1) is a sulfur-containing peptide antibiotic obtained through fermentation. It exerts exceptional antibiotic activity in vitro and in a mouse model against critical Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) or Clostridium difficile. The first total synthesis of nosiheptide was reported, utilizing double macro-cyclization of a fully-functionalized linear precursor [6]. Strong motivation exists to dynamically-optimize the process for improved product yield while reducing production time and cost to improve the industrial relevancy of manufacturing this antibiotic [7,8]
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