Zhiyu Zang, Olivia K. Duncan, Dziugas Sabonis, Iana Fedorova, Yun Shi, Gause Miraj, Shuai Le, Jun Deng, Yuhao Zhu, Yanyao Cai, Chengqian Zhang, Garima Arya, Shelley A.H. Dixon, Steven P. Angus, Breck A. Duerkop, Haihua Liang, Robert H. Pepin, Thomas Ve, Joseph Bondy-Denomy, Giedrė Tamulaitienė, Joseph P. Gerdt
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.