Chemical inactivation of a bacterial immune system de-domesticates a temperate phage and promotes its spread

Microbial communities shape hosts and ecosystems, yet the behaviors of these microbes are themselves controlled by mobile genetic elements. These mobile genetic elements (MGEs) compete and influence one another’s distributions. For example, many anti-phage immune systems are carried by prophages, plasmids, and integrative and conjugative elements (ICEs). It is unclear how important each of these interference mechanisms is for the spread of different mobile elements. Chemical inhibitors of these mechanisms of inter-MGE competition can clarify their mechanisms and significance in diverse environments. We discovered chemical inhibitors of SpbK—an antiphage defense encoded by an ICE in several strains of Bacillus subtilis . It is believed to prevent the dissemination of SPβ -like temperate phages, forcing SPβ to remain ‘domesticated’ in its ICE-containing host. Chemical inhibition of SpbK dramatically improved the escape of infectious SPβ phages capable of disseminating and forming new lysogens. Furthermore, SpbK is part of a widespread class of Toll/interleukin-1 receptor (TIR)-domain containing enzymes that are prevalent both in prokaryotic antiphage immune systems and eukaryotic immune signaling. Our inhibitors reveal two distinct mechanisms of inhibiting TIR-domain enzymes. These models of inhibition may broadly apply across immune proteins, enabling inhibition of many TIR immune systems that influence phage spread as well as plant immunity and animal cellular signaling.