Simultaneous design of fermentation and microbe

TL;DR

This paper introduces SimulKnock, a bilevel optimization method that simultaneously designs microbial strains and fermentation processes, leading to higher yields than sequential approaches.

Contribution

The paper presents a novel bilevel optimization framework that integrates strain and process design, improving bioprocess performance compared to traditional sequential methods.

Findings

SimulKnock achieves higher space-time yields than OptKnock in a case study.

SimulKnock predicts optimal gene deletions balancing growth and production.

The integrated approach reduces the gap between strain and process optimization.

Abstract

Constraint-based optimization of microbial strains and model-based bioprocess design have been used extensively to enhance yields in biotechnological processes. However, strain and process optimization are usually carried out in sequential steps, causing underperformance of the biotechnological process when scaling up to industrial fermentation conditions. Herein, we propose the optimization formulation SimulKnock that combines the optimization of a fermentation process with metabolic network design in a bilevel optimization program. The upper level maximizes space-time yield and includes mass balances of a continuous fermentation, while the lower level is based on flux balance analysis. SimulKnock predicts optimal gene deletions and finds the optimal trade-off between growth rate and product yield. Results of a case study with a genome-scale metabolic model of E. coli indicate higher space-time yields than a sequential approach using OptKnock for almost all target products considered. By leveraging SimulKnock, we reduce the gap between strain and process optimization.