Use of a simple mathematical model to predict the behavior of Escherichia coli overproducing beta-lactamase within continuous single- and two-stage reactor systems

A simple mathematical model is developed to help explain the complex population dynamics of an Escherichia coli host-plasmid expression/excretion system for beta-lactamase within single- and two-stage reactors. The model successfully integrates the individual regulatory (tac promoter induction), genetic (runaway plasmid replication), and population dynamics (culture instability) aspects of the system. The model predicts, and experiment confirms, that high-level beta-lactamase production and excretion cannot be easily maintained in single-stage reactors using the current plasmid construction. Stable target protein production and excretion is mathematically predicted, and experimentally confirmed, within two-stage reactors. The model is used to provide insight into engineering a more stable host-vector expression/excretion system for use in single-stage reactors. (c) 1993 John Wiley & Sons, Inc.