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Drug interactions are complex because one drug may affect\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      ) 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\u2019s effect on bacterial cellular processes. SEARCH-TB is a novel pharmacodynamic (PD) approach that uses targeted\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      transcriptional profiling to evaluate drug effects on\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      physiology. To evaluate SEARCH-TB\u2019s 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\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">in vivo,<\/jats:italic>\n                      providing information distinct from CFU burden and suggesting a future where regimen selection is informed by\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      molecular measures of\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      physiology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00492-25","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T14:50:53Z","timestamp":1758207053000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Deconvoluting drug interactions using\n                    <i>M. tuberculosis<\/i>\n                    physiologic processes: transcriptional disaggregation of the BPaL regimen\n                    <i>in vivo<\/i>"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5857-4483","authenticated-orcid":false,"given":"Elizabeth A.","family":"Wynn","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/016z2bp30","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Genes, Environment and Health, National Jewish Health","place":["Denver, USA"]},{"name":"Rocky Mountain Regional VA Medical Center","place":["Aurora, USA"]},{"name":"Consortium for Applied Microbial Metrics","place":["Aurora, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Dide-Agossou","sequence":"additional","affiliation":[{"name":"Rocky Mountain Regional VA Medical Center","place":["Aurora, USA"]},{"name":"Consortium for Applied Microbial Metrics","place":["Aurora, 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