Closing the Loop on Phage-bacteria Coevolution

Abstract

Bacteria and their viruses, bacteriophages (phages), continually coevolve in nature. In contrast, laboratory-based coevolution experiments usually last less than a month before becoming dormant or extinct as one species is outcompeted by the other. Consequently, there is a poor understanding of phage-bacteria coevolution and hence the long-term efficacy of bacteriophage therapies (an approach to tackling antimicrobial resistance). We propose a novel approach to coevolution experiments that would address this challenge: instead of open-loop resource-constrained cultures, we develop a closed-loop control approach to stabilise the typically unstable or oscillatory phage-bacteria population dynamics. Achieving this requires the control system to compensate for delays in phage incubation and respond to an evolving system, while only measuring bacterial density. To this end, we develop a model of phage-bacteria dynamics, prototype delay-compensating predictive control strategies, and demonstrate a measurement-aware state observer. Overall, this approach shows the ability to stabilise coevolution, avoiding the common outcomes of unstable dynamics or winner-takes-all competition.