Rapid resistance evolution against phage cocktails

When bacteria are treated with multiple antibiotics simultaneously, resistance is highly unlikely to evolve. In stark contrast, resistance against multiple phages frequently arises during therapy. Why does resistance against multi-phage cocktails evolve so easily? Using a mathematical model, we show how the bacterial evolutionary dynamics and phage replicative dynamics uniquely intertwine, facilitating the rapid evolution of multi-phage resistance. As different phages replicate and become inhibitory at varying time points, bacteria can sequentially acquire resistance rather than simultaneously - increasing the chance of multi-resistance by orders of magnitude. Additionally, we predict and experimentally verify a regime where multi-phage resistance is robustly prevented. Our findings provide a framework for the rational design of phage cocktails to curtail resistance development. Resistance can be minimized by reducing the dose of the most potent phages or by using phages with longer latent periods, as this helps synchronize multi-phage selection.