Chemical inhibition of a bacterial immune system

Zang, Z.; Duncan, O. K.; Sabonis, D.; Shi, Y.; Miraj, G.; Fedorova, I.; Le, S.; Deng, J.; Zhu, Y.; Cai, Y.; Zhang, C.; Arya, G.; Duerkop, B. A.; Liang, H.; Bondy-Denomy, J.; Ve, T.; Tamulaitiene, G.; Gerdt, J. P.

doi:10.1101/2025.02.20.638879

bioRxiv · 10.1101/2025.02.20.638879

Chemical inhibition of a bacterial immune system

Zang, Z.·Duncan, O. K.·Sabonis, D.·Shi, Y.·Miraj, G.·Fedorova, I.·Le, S.·Deng, J.·Zhu, Y.·Cai, Y.·Zhang, C.·Arya, G.·Duerkop, B. A.·Liang, H.·Bondy-Denomy, J.·Ve, T.·Tamulaitiene, G.·Gerdt, J. P.

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Abstract

The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens of anti-bacteriophage 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 that anti-phage systems can be selectively inhibited by small molecules, thereby sensitizing phage-resistant bacteria to phages. We discovered a class of chemical inhibitors that inhibit the type II Thoeris anti-phage immune system. These inhibitors block the biosynthesis of a histidine-ADPR intracellular alarm signal by ThsB and prevent ThsA from arresting phage replication. These inhibitors promiscuously inhibit type II Thoeris systems from diverse bacteria--including antibiotic-resistant pathogens. Chemical inhibition of the Thoeris defense improved the efficacy of a model phage therapy against a phage-resistant strain of P. aeruginosa in a mouse infection, suggesting a therapeutic potential. Furthermore, these inhibitors may be employed as chemical tools to dissect the importance of the Thoeris system for phage defense in natural microbial communities.

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Zang, Z., Duncan, O. K., Sabonis, D., Shi, Y., Miraj, G., Fedorova, I., Le, S., Deng, J., Zhu, Y., Cai, Y., Zhang, C., Arya, G., Duerkop, B. A., Liang, H., Bondy-Denomy, J., Ve, T., Tamulaitiene, G., Gerdt, J. P.. 2025-02-21. Chemical inhibition of a bacterial immune system. https://doi.org/10.1101/2025.02.20.638879

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