Genetic hurdles limit the arms race between Prochlorococcus and the T7-like podoviruses infecting them.

Phages and hosts coexist in nature with a high degree of population diversity. This is often explained through coevolutionary models, such as the arms race or density-dependent fluctuating selection, which differ in assumptions regarding the emergence of phage mutants that overcome host resistance. Previously, resistance in the abundant marine cyanobacterium, Prochlorococcus, was found to occur frequently. However, little is known about the ability of phages to overcome this resistance. Here we report that, in some cases, T7-like cyanophage mutants emerge to infect resistant Prochlorococcus strains. These resistance-breaking phages retained the ability to infect the wild-type host. However, fitness of the mutant phages differed on the two hosts. Furthermore, in one case, resistance-breaking was accompanied by costs of decreased fitness on the wild-type host and decreased adsorption specificity, relative to the wild-type phage. In two other cases, fitness on the wild-type host increased. Whole-genome sequencing revealed mutations in probable tail-related genes. These were highly diverse in isolates and natural populations of T7-like cyanophages, suggesting that antagonistic coevolution enhances phage genome diversity. Intriguingly, most interactions did not yield resistance-breaking phages. Thus, resistance mutations raise genetic barriers to continuous arms race cycles and are indicative of an inherent asymmetry in coevolutionary capacity, with hosts having the advantage. Nevertheless, phages coexist with hosts, which we propose relies on combined, parallel action of a limited arms race, fluctuating selection and passive host-switching within diverse communities. Together, these processes generate a constantly changing network of interactions, enabling stable coexistence between hosts and phages in nature.