Multi-strain phage-induced clearance of Pseudomonas aeruginosa

Antibiotic resistant bacteria are a serious global health threat. As a

result, phages – viruses that exclusively infect and

lyse bacteria – are increasingly considered as a therapeutic

alternative to treat bacterial infections. But, bacteria can develop

resistance against phages during treatment leading to adverse clinical

outcomes. Mixtures of multiple phages (i.e., 'cocktails') have been

proposed as a means to minimize the chance that the emergence of a

phage-resistant bacterial mutant leads to therapeutic failure. Here, we

address quantitatively how to design a phage cocktail efficient against

Pseudomonas aeruginosa infections. We study the efficacy of a cocktail

composed of two phages that bind to different bacterial receptors, via a

combination of vitro experiments and nonlinear dynamics models. We show

that the phage cocktail can control the bacterial population and utilize

model-data comparisons to shed light on physiological mechanisms

underlying emergent population dynamics. We leverage these findings to

analyze a theoretical model of in vivo infection dynamics, where

therapeutic phage and the innate immune system can work synergistically to

prevent infection. We quantify the therapy outcome in a single- or

double-phage treatment as a function of phage traits and immune strength.