Chemical 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.
Authors
- Giedrė Tamulaitienė (ORCID: https://orcid.org/0000-0002-9794-3544)
- Karen E. Knudsen (ORCID: https://orcid.org/0000-0002-1301-890X)
- Zhiyu Zang (ORCID: https://orcid.org/0000-0002-4879-7077)
- Joseph P. Gerdt (ORCID: https://orcid.org/0000-0002-0375-4110)
- Breck A. Duerkop (ORCID: https://orcid.org/0000-0003-4030-9822)
- Shelley A.H. Dixon
- Dziugas Sabonis
- Jinchao Zhang (ORCID: https://orcid.org/0000-0003-4611-9675)
- Gause Miraj
- Thomas Ve
- Jun Deng
- Yuhao Zhu
- Joseph Bondy-Denomy
- Garima Arya
- Yun Shi
- Robert H. Pepin
- Iana Fedorova
- Yanyao Cai
- Shuai Le
- Olivia K. Duncan
Institutions
- Griffith University (AU)
- Army Medical University (CN)
- Vilnius University (LT)
- University of California, San Francisco (US)
- Southern University of Science and Technology (CN)
- Indiana University Bloomington (US)
- Indiana University School of Medicine
- University of Colorado Anschutz Medical Campus (US)
- Indiana University – Purdue University Indianapolis (US)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2026-01-30
- DOI
- https://doi.org/10.1016/j.chom.2026.01.003
- Primary Topic
- Bacteriophages and microbial interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Ohio State University
- American Society of Pharmacognosy
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council