{"doi":"10.1128/aac.00492-25","title":"Deconvoluting drug interactions using <i>M. tuberculosis</i> physiologic processes: transcriptional disaggregation of the BPaL regimen <i>in vivo</i>","abstract":"ABSTRACT A key challenge in preclinical tuberculosis drug development is identifying optimal antibiotic combinations. Drug interactions are complex because one drug may affect Mycobacterium tuberculosis ( Mtb ) physiology in a way that alters the activity of another drug. Conventional pharmacodynamic evaluation based on colony-forming units (CFU) does not provide information about this physiologic interaction because CFU enumerates bacteria but does not give information about the drug’s effect on bacterial cellular processes. SEARCH-TB is a novel pharmacodynamic (PD) approach that uses targeted in vivo transcriptional profiling to evaluate drug effects on Mtb physiology. To evaluate SEARCH-TB’s capacity to elucidate drug interactions, we deconstructed the BPaL (bedaquiline, pretomanid, and linezolid) regimen in the BALB/c high-dose aerosol mouse infection model, measuring the effect of 2-, 7-, and 14-day treatment with drugs in monotherapy, pairwise combinations, and as a three-drug combination. Monotherapy induced drug-specific Mtb transcriptional responses by day 2 with continued evolution over 14 days. Bedaquiline dominated pairwise combinations with pretomanid and linezolid, whereas the pretomanid-linezolid combination induced a transcriptional profile intermediate between either drug. In the three-drug BPaL regimen, adding both pretomanid and linezolid to bedaquiline yielded a greater transcriptional response than expected, based on pairwise results. This work demonstrates that physiologic perturbations induced by a single drug may be modified in complex ways when drugs are combined. This establishes proof of concept that SEARCH-TB provides a highly granular readout of drug interactions in vivo, providing information distinct from CFU burden and suggesting a future where regimen selection is informed by in vivo molecular measures of Mtb physiology.","journal":"Antimicrobial Agents and Chemotherapy","year":2025,"id":575196,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":true,"deposit_databanks":{"BioProject":["PRJNA1240236","SAMN47511482","SAMN47511591"],"SRA":["PRJNA1240236","SAMN47511482","SAMN47511591"]},"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":638084,"name":"Christian Dide-Agossou","orcid":"0000-0001-9854-1785","position":1,"is_corresponding":false},{"id":763353,"name":"Reem Al Mubarak","orcid":"0000-0002-2303-7004","position":2,"is_corresponding":false},{"id":638086,"name":"Karen Rossmassler","orcid":"0000-0003-4069-744X","position":3,"is_corresponding":false},{"id":415204,"name":"Jo Hendrix","orcid":null,"position":4,"is_corresponding":false},{"id":638098,"name":"Martin I. Voskuil","orcid":"0000-0002-9565-7923","position":5,"is_corresponding":false},{"id":394808,"name":"Andrés Obregón‐Henao","orcid":"0000-0002-6496-6790","position":6,"is_corresponding":false},{"id":1247317,"name":"Michael A. Lyons","orcid":"0000-0003-0143-6626","position":7,"is_corresponding":false},{"id":477426,"name":"Gregory T. Robertson","orcid":"0000-0001-7157-4034","position":8,"is_corresponding":false},{"id":407619,"name":"Camille M. Moore","orcid":"0000-0002-7363-8684","position":9,"is_corresponding":false},{"id":511597,"name":"Nicholas D. Walter","orcid":"0000-0003-0126-1993","position":10,"is_corresponding":false},{"id":1071955,"name":"Elizabeth A. Wynn","orcid":"0000-0002-5857-4483","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:57:48.486077Z","pmid":"40965512","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":[]}