{"doi":"10.1101/2025.02.20.638879","title":"Chemical inhibition of a bacterial immune system","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554951,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1453198,"name":"Olivia K. Duncan","orcid":null,"position":1,"is_corresponding":false},{"id":1453199,"name":"Dziugas Sabonis","orcid":null,"position":2,"is_corresponding":false},{"id":618458,"name":"Yun Shi","orcid":"0000-0003-3365-4679","position":3,"is_corresponding":false},{"id":1453200,"name":"Gause Miraj","orcid":null,"position":4,"is_corresponding":false},{"id":1030605,"name":"Iana Fedorova","orcid":"0000-0001-6144-173X","position":5,"is_corresponding":false},{"id":246143,"name":"Shuai Le","orcid":"0000-0003-3748-5454","position":6,"is_corresponding":false},{"id":1452791,"name":"Jun Deng","orcid":"0000-0003-2420-8079","position":7,"is_corresponding":false},{"id":1452792,"name":"Yuhao Zhu","orcid":"0000-0001-5425-0986","position":8,"is_corresponding":false},{"id":1304851,"name":"Yanyao Cai","orcid":null,"position":9,"is_corresponding":false},{"id":1327937,"name":"Chengqian Zhang","orcid":"0009-0005-5329-6655","position":10,"is_corresponding":false},{"id":1195894,"name":"Garima Arya","orcid":null,"position":11,"is_corresponding":false},{"id":241737,"name":"Breck A. Duerkop","orcid":"0000-0003-4030-9822","position":12,"is_corresponding":false},{"id":397047,"name":"Haihua Liang","orcid":"0000-0001-9639-1867","position":13,"is_corresponding":false},{"id":238123,"name":"Joseph Bondy‐Denomy","orcid":"0000-0002-4909-9481","position":14,"is_corresponding":false},{"id":74942,"name":"Thomas Ve","orcid":"0000-0002-0113-1905","position":15,"is_corresponding":false},{"id":1452793,"name":"Giedrė Tamulaitienė","orcid":"0000-0002-9794-3544","position":16,"is_corresponding":false},{"id":832115,"name":"Joseph P. Gerdt","orcid":"0000-0002-0375-4110","position":17,"is_corresponding":false},{"id":1327936,"name":"Zhiyu Zang","orcid":"0000-0002-4879-7077","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:54:54.542303Z","pmid":"40027640","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}