Phage anti-defense genes targeting NAD + metabolism and DNA replication are associated with a broad host range against Klebsiella pneumoniae

. Deletion of these genes collapsed the host spectrum from 109 strains to fewer than 10, significantly compromising antibacterial efficacy. The wild-type phage substantially improves survival in a mouse bacteremia model. Our study identifies candidate genetic factors associated with the broad host range phenotype, specifically targeting host immunity, and provides a new strategy for engineering therapeutic phages.