Abstract
Cost effective and scalable methods for phage production are required to meet an increasing demand for phage, as an alternative to antibiotics. Computational models can assist the optimization of such production processes. A model is developed here that can simulate the dynamics of phage population growth and production in a two-stage, self-cycling process. The model incorporates variable infection parameters as a function of bacterial growth rate and employs ordinary differential equations, allowing application to a setup with multiple reactors. The model provides simple cost estimates as a function of key operational parameters including substrate concentration, feed volume and cycling times. For the phage and bacteria pairing examined, costs and productivity varied by three orders of magnitude, with the lowest cost found to be most sensitive to the influent substrate concentration and low level setting in the first vessel. An example case study of phage production is also presented, showing how parameter values affect the production costs and estimating production times. The approach presented is flexible and can be used to optimize phage production at laboratory or factory scale by minimizing costs or maximizing productivity.
Highlights
The application of phages in areas such as medicine and food science is a viable alternative to antibiotics that can potentially avoid the problem of multi-drug resistant bacteria
We introduce some useful concepts for modelling phage production and develop a computational model that can be used to assist optimization of phage production processes
To illustrate the potential improvement in accuracy with a model that incorporates variable infection parameters, we performed simulations of a batch process using the basic model described in Equations (5)–(8) and the proposed improved model described in Equations (13)–(19) (Supplementary Figure S1)
Summary
The application of phages in areas such as medicine and food science is a viable alternative to antibiotics that can potentially avoid the problem of multi-drug resistant bacteria This treatment strategy has received increased attention during the past decade and currently, phages are applied in medicine to treat bacterial infections and in food processing to prevent the contamination of meats [1,2]. Other areas that are actively being explored include the prevention of pipeline corrosion in fracking and the prevention of unwanted foaming in wastewater treatment [3,4] The scale of these latter applications may require high quantities of phages if the infection rate and phage reproduction rate are low, which is often the case in an environmental setting where nutrient levels are limited [5,6]. Such facilities will have a commercial interest in process and cost optimization
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