| Title |
Chemical inhibition of a bacterial immune system |
| Authors |
Zang, Zhiyu ; Duncan, Olivia K ; Sabonis, Džiugas ; Fedorova, Iana ; Shi, Yun ; Miraj, Gause ; Le, Shuai ; Deng, Jun ; Zhu, Yuhao ; Cai, Yanyao ; Zhang, Chengqian ; Arya, Garima ; Dixon, Shelley A.H ; Angus, Steven P ; Duerkop, Breck A ; Liang, Haihua ; Pepin, Robert H ; Ve, Thomas ; Bondy-Denomy, Joseph ; Tamulaitienė, Giedrė ; Gerdt, Joseph P |
| DOI |
10.1016/j.chom.2026.01.003 |
| Full Text |
|
| Is Part of |
Cell host & microbe.. Cambridge : Elsevier Inc.. 2026, vol. 34, iss. 2, p. 263-277, e1-e11.. ISSN 1931-3128. eISSN 1934-6069 |
| Keywords [eng] |
anti-phage defense system ; bacteriophage ; bacterial immunity ; Thoeris systemchemical inhibitorphage therapy ; Pseudomonas aeruginosa ; antibacterial adjuvant ; antibiotic resistance |
| Abstract [eng] |
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. |
| Published |
Cambridge : Elsevier Inc |
| Type |
Journal article |
| Language |
English |
| Publication date |
2026 |
| CC license |
|
