biostudies-literatureZang ZKey Technologies Research and Development ProgramRobert J Kleberg Jr and Helen C Kleberg FoundationNCATS NIH HHSNIAID NIH HHSCamille and Henry Dreyfus Foundation IncNational Institutes of HealthNIGMS NIH HHSNational Science FoundationAustralian Research Council263-277.e11https://www.ebi.ac.uk/biostudies/studies/S-EPMC12866962biostudies-literatureUnknown34(2)The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens of anti-phage immune systems that confer resistance to therapeutic phages. Chemical inhibitors of these anti-phage immune systems could be employed as adjuvants to overcome resistance in phage-based therapies. Here, we report a class of chemical inhibitors that selectively inhibit type II Thoeris anti-phage immune systems from diverse bacteria-including antibiotic-resistant pathogens, thereby sensitizing phage-resistant bacteria to phages. These inhibitors block the biosynthesis of a histidine-ADPR intracellular "alarm" signal by ThsB, thereby preventing ThsA from arresting phage replication. Chemical inhibition of the Thoeris defense improves the efficacy of a model phage therapy against a phage-resistant clinical isolate of P. aeruginosa in a mouse infection, suggesting a therapeutic potential. These findings demonstrate that the selective inhibition of anti-phage defense systems can improve the efficacy of therapeutic phages, suggesting a strategy to circumvent phage-therapy resistance.Cell host & microbeChemical inhibition of a bacterial immune system.PMC12866962TL1 TR002531R01 AI141479R35 GM138376Fedorova IZang ZZhu YGerdt JPMiraj GAngus SPLe SDeng JArya GVe TSabonis DShi YDixon SAHTamulaitiene GDuncan OKLiang HCai YPepin RHZhang CDuerkop BABondy-Denomy JfalseChemical inhibition of a bacterial immune system.The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens of anti-phage immune systems that confer resistance to therapeutic phages. Chemical inhibitors of these anti-phage immune systems could be employed as adjuvants to overcome resistance in phage-based therapies. Here, we report a class of chemical inhibitors that selectively inhibit type II Thoeris anti-phage immune systems from diverse bacteria-including antibiotic-resistant pathogens, thereby sensitizing phage-resistant bacteria to phages. These inhibitors block the biosynthesis of a histidine-ADPR intracellular "alarm" signal by ThsB, thereby preventing ThsA from arresting phage replication. Chemical inhibition of the Thoeris defense improves the efficacy of a model phage therapy against a phage-resistant clinical isolate of P. aeruginosa in a mouse infection, suggesting a therapeutic potential. These findings demonstrate that the selective inhibition of anti-phage defense systems can improve the efficacy of therapeutic phages, suggesting a strategy to circumvent phage-therapy resistance.2026-01-01T00:00:00Z2026 Feb2026-07-04T03:20:49.693Z2026-07-04T03:12:01.699ZS-EPMC128669624161973810.1016/j.chom.2026.01.003