As an alternative to traditional antibiotics that kill bacteria, we can interfere with bacterial virulence. Bacteria have many proteins that contain the so-called TIR (Toll/interleukin-1 receptor) domains, which are also found widely in animals and plants and are usually associated with immune functions. Recent work shows that many bacterial TIR-domain proteins are associated with antiphage defense, and some have been implicated as virulence factors. An emerging molecular function of bacterial TIR domains is enzymatic activity associated with cleavage of NAD+. These functions of bacterial TIR domain-containing proteins make them potential antibacterial drug targets.