The life history traits of phages in a cocktail determine coinfection dynamics and efficacy

Phage cocktails are preferred over single phages for efficacious and broader-spectrum therapy. An ideal phage cocktail should have a minimum number of phages with efficient infection kinetics and delay the emergence of resistance in bacterial populations. This study examined population dynamics of the common host and combinations of two phages (N4, KKE5P, and Ec_YwIITB1) through experimental and modeling approaches to gaining insights into how phage life history traits influence the outcome of infection in the short-term of approximately an infection cycle, and whether it is informative for developing efficacious cocktails. We tested the killing efficacy of a cocktail containing two divergent phages (N4 and Ec_YwIITB1) with similar adsorption rates but differed in their latency period. Because of the shorter latency period, phage N4 dominated under all conditions tested. The cocktail essentially behaves as a single phage. When two phages (N4 and KKE5P), with similar adsorption rates and latency periods but targeted different host receptors were used, it not only resulted in the efficient replication of both phages but also improved the suppression of the emergence of resistance when compared to the N4 and Ec_YwIITB1 combination, thus behaving like an ideal cocktail. The ODE-based mathematical model demonstrated predictive capabilities consistent with experimental observations and offered insights into infection dynamics. The model may aid in phage selection and optimizing cocktail formulation based on phage life history traits. This study highlights the need for thorough characterization of phage growth parameters and informed combinations of phages, as random combinations could lead to undesirable outcomes.