Chemical suppression of a bacterial immune system revives repressed phages

Many antiviral immune systems have recently been discovered in bacteria. The mechanisms of several are obscure, as are their individual significance for antiphage defense. To shed light on the mechanism and significance of the two-component type I Thoeris antiphage immune system, we leveraged high-throughput phenotypic screening to identify three small molecule inhibitors. The inhibitors target the ThsA NADase component, inhibiting its 3ʹ-cADPR-activated filamentation. The temporal control afforded by the small-molecule inhibitors allowed us to answer an outstanding question in antiviral immunity—is persistent immunity required to repress phage titers, or do immune systems become unnecessary after eradicating infectious phages? We found that Thoeris immunity must be maintained, as chemical inhibition enabled repressed phages to revive and overtake the bacterial population. Furthermore, due to the cooperative nature of antiviral immunity, we found that Thoeris must be inhibited in only 10% of the bacteria to cause phage-induced lysis of the entire population.