SUMMARYThe 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. C... More
SUMMARYThe 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.Graphical AbstracteTOC:Bacteriophages are promising alternatives to antibiotics for treating bacterial infections. However, bacteria possess immune systems that neutralize bacteriophages. Zang et al. discover small molecules that inhibit one such anti-viral defense system, thereby resensitizing bacteria to bacteriophages in mouse infection models and complex polymicrobial communities.
