{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:47:50Z","timestamp":1785548870228,"version":"3.56.0"},"posted":{"date-parts":[[2024,8,21]]},"group-title":"Genomics","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T00:00:00Z","timestamp":1724198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  A major challenge in tuberculosis (TB) therapeutics is that antibiotic exposure leads to changes in the physiologic state of\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  (\n                  <jats:italic>Mtb<\/jats:italic>\n                  ) which may enable the pathogen to withstand treatment. While antibiotic-treated\n                  <jats:italic>Mtb<\/jats:italic>\n                  have been evaluated in short-term\n                  <jats:italic>in vitro<\/jats:italic>\n                  experiments, it is unclear if and how long-term\n                  <jats:italic>in vivo<\/jats:italic>\n                  treatment with diverse antibiotics with varying treatment-shortening activity (sterilizing activity) affect\n                  <jats:italic>Mtb<\/jats:italic>\n                  physiologic states differently. Here, we used SEARCH-TB, a pathogen-targeted RNA-sequencing platform, to characterize the\n                  <jats:italic>Mtb<\/jats:italic>\n                  transcriptome in the BALB\/c high-dose aerosol infection mouse model following 4-week treatment with three sterilizing and three non-sterilizing antibiotics. Certain transcriptional changes were concordant among most antibiotics, including decreased expression of genes associated with protein synthesis and metabolism, and the induction of certain genes associated with stress responses. However, the magnitude of this concordant response differed between antibiotics. Sterilizing antibiotics rifampin, pyrazinamide, and bedaquiline generated a more quiescent\n                  <jats:italic>Mtb<\/jats:italic>\n                  state than did non-sterilizing antibiotics isoniazid, ethambutol, and streptomycin, as indicated by decreased expression of genes associated with translation, transcription, secretion of immunogenic proteins, metabolism, and cell wall synthesis. Additionally, we identified distinguishing transcriptional effects specific to each antibiotic, indicating that different mechanisms of action induce distinct patterns of cellular injury. In addition to elucidating\n                  <jats:italic>Mtb<\/jats:italic>\n                  physiologic changes associated with antibiotic stress, this study demonstrates the value of SEARCH-TB as a highly granular pharmacodynamic assay that reveals antibiotic effects that are not apparent based on culture alone.\n                <\/jats:p>","DOI":"10.1101\/2024.08.20.607990","type":"posted-content","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T06:10:17Z","timestamp":1724652617000},"source":"Crossref","is-referenced-by-count":2,"title":["Emergence of antibiotic-specific\n                  <i>Mycobacterium tuberculosis<\/i>\n                  phenotypes during prolonged treatment of mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5857-4483","authenticated-orcid":false,"given":"Elizabeth A","family":"Wynn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Dide-Agossou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Al Mubarak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Rossmassler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Ektnitphong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison A","family":"Bauman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M","family":"Massoudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin I","family":"Voskuil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory T","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille M","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024082603100942000_2024.08.20.607990v1.1","unstructured":"World Health Organization. Global tuberculosis report 2020. (2020)."},{"key":"2024082603100942000_2024.08.20.607990v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw376"},{"key":"2024082603100942000_2024.08.20.607990v1.3","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41579-022-00731-y","article-title":"Anti-tuberculosis treatment strategies and drug development: Challenges and priorities","volume":"20","year":"2022","journal-title":"Nature Reviews Microbiology"},{"key":"2024082603100942000_2024.08.20.607990v1.4","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/s41579-022-00700-5","article-title":"The physiology and genetics of bacterial responses to antibiotic combinations","volume":"20","year":"2022","journal-title":"Nature Reviews Microbiology"},{"key":"2024082603100942000_2024.08.20.607990v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12252"},{"key":"2024082603100942000_2024.08.20.607990v1.6","doi-asserted-by":"crossref","unstructured":"Sarathy, J. P. et al. Extreme drug tolerance of mycobacterium tuberculosis in caseum. Antimicrob. Agents Chemother. 62, (2018).","DOI":"10.1128\/AAC.02266-17"},{"key":"2024082603100942000_2024.08.20.607990v1.7","doi-asserted-by":"crossref","first-page":"102318","DOI":"10.1016\/j.tube.2023.102318","article-title":"Adaptation to the intracellular environment of primary human macrophages influences drug susceptibility of Mycobacterium tuberculosis","volume":"139","year":"2023","journal-title":"Tuberculosis"},{"key":"2024082603100942000_2024.08.20.607990v1.8","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1089\/mdr.2020.0179","article-title":"Differential Isoniazid Response Pattern between Active and Dormant Mycobacterium tuberculosis","volume":"27","year":"2021","journal-title":"Microb. Drug Resist"},{"key":"2024082603100942000_2024.08.20.607990v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4369"},{"key":"2024082603100942000_2024.08.20.607990v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2003.12.005"},{"key":"2024082603100942000_2024.08.20.607990v1.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406796200"},{"key":"2024082603100942000_2024.08.20.607990v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.22.12833"},{"key":"2024082603100942000_2024.08.20.607990v1.13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006077"},{"key":"2024082603100942000_2024.08.20.607990v1.14","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.02779.x"},{"key":"2024082603100942000_2024.08.20.607990v1.15","doi-asserted-by":"crossref","unstructured":"Poonawala, H. et al. Transcriptomic responses to antibiotic exposure in Mycobacterium tuberculosis . Antimicrob. Agents Chemother. 68, (2024).","DOI":"10.1128\/aac.01185-23"},{"key":"2024082603100942000_2024.08.20.607990v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02363-23"},{"key":"2024082603100942000_2024.08.20.607990v1.17","doi-asserted-by":"publisher","DOI":"10.1378\/chest.76.6.771"},{"key":"2024082603100942000_2024.08.20.607990v1.18","first-page":"796","article-title":"Role of individual drugs in the chemotherapy of tuberculosis","volume":"4","year":"2000","journal-title":"Int. J. Tuberc. Lung Dis"},{"key":"2024082603100942000_2024.08.20.607990v1.19","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv183"},{"key":"2024082603100942000_2024.08.20.607990v1.20","doi-asserted-by":"crossref","unstructured":"Love, M. I. , Huber, W. & Anders, S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2024082603100942000_2024.08.20.607990v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2024082603100942000_2024.08.20.607990v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s00357-014-9161-z"},{"key":"2024082603100942000_2024.08.20.607990v1.23","doi-asserted-by":"crossref","unstructured":"Cole, S. T. et al. Erratum: Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 396, 190 (1998).","DOI":"10.1038\/24206"},{"key":"2024082603100942000_2024.08.20.607990v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz700"},{"key":"2024082603100942000_2024.08.20.607990v1.25","doi-asserted-by":"publisher","DOI":"10.1177\/0748730414553029"},{"key":"2024082603100942000_2024.08.20.607990v1.26","doi-asserted-by":"crossref","unstructured":"Zhang, N. et al. Mechanistic modeling of Mycobacterium tuberculosis infection in murine models for drug and vaccine efficacy studies. Antimicrob. Agents Chemother. 64, (2020).","DOI":"10.1128\/AAC.01727-19"},{"key":"2024082603100942000_2024.08.20.607990v1.27","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.13022"},{"key":"2024082603100942000_2024.08.20.607990v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2019.12.001"},{"key":"2024082603100942000_2024.08.20.607990v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2017.08.040"},{"key":"2024082603100942000_2024.08.20.607990v1.30","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.pbiomolbio.2019.11.002","article-title":"Cytochrome bd in Mycobacterium tuberculosis: A respiratory chain protein involved in the defense against antibacterials","volume":"152","year":"2020","journal-title":"Progress in Biophysics and Molecular Biology"},{"key":"2024082603100942000_2024.08.20.607990v1.31","doi-asserted-by":"crossref","unstructured":"Nandakumar, M. , Nathan, C. & Rhee, K. Y . Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis . Nat. Commun. 5, (2014).","DOI":"10.1038\/ncomms5306"},{"key":"2024082603100942000_2024.08.20.607990v1.32","first-page":"0634","article-title":"Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum","volume":"5","year":"2008","journal-title":"PLoS Med"},{"key":"2024082603100942000_2024.08.20.607990v1.33","doi-asserted-by":"crossref","unstructured":"Quigley, J. et al. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of Mycobacterium tuberculosis . MBio 8, (2017).","DOI":"10.1128\/mBio.00148-17"},{"key":"2024082603100942000_2024.08.20.607990v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2021.102162"},{"key":"2024082603100942000_2024.08.20.607990v1.35","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv149"},{"key":"2024082603100942000_2024.08.20.607990v1.36","doi-asserted-by":"crossref","first-page":"588487","DOI":"10.3389\/fmicb.2020.588487","article-title":"The partner switching system of the SigF sigma factor in Mycobacterium smegmatis and induction of the SigF regulon under respiration-inhibitory conditions","volume":"11","year":"2020","journal-title":"Front. Microbiol"},{"key":"2024082603100942000_2024.08.20.607990v1.37","doi-asserted-by":"crossref","unstructured":"Chauhan, R. et al. Reconstruction and topological characterization of the sigma factor regulatory network of Mycobacterium tuberculosis . Nat. Commun. 7, (2016).","DOI":"10.1038\/ncomms11062"},{"key":"2024082603100942000_2024.08.20.607990v1.38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001502"},{"key":"2024082603100942000_2024.08.20.607990v1.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0040120"},{"key":"2024082603100942000_2024.08.20.607990v1.40","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.000760"},{"key":"2024082603100942000_2024.08.20.607990v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20241-w"},{"key":"2024082603100942000_2024.08.20.607990v1.42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700515"},{"key":"2024082603100942000_2024.08.20.607990v1.43","doi-asserted-by":"crossref","unstructured":"Jamaati, H. et al. Nitric oxide in the pathogenesis and treatment of tuberculosis. Frontiers in Microbiology 8, 281243 (2017).","DOI":"10.3389\/fmicb.2017.02008"},{"key":"2024082603100942000_2024.08.20.607990v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620133114"},{"key":"2024082603100942000_2024.08.20.607990v1.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1523321113"},{"key":"2024082603100942000_2024.08.20.607990v1.46","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.addr.2016.01.014","article-title":"Challenges in the clinical assessment of novel tuberculosis drugs","volume":"102","year":"2016","journal-title":"Advanced Drug Delivery Reviews"},{"key":"2024082603100942000_2024.08.20.607990v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2007.12.002"},{"key":"2024082603100942000_2024.08.20.607990v1.48","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200905-0661OC"},{"key":"2024082603100942000_2024.08.20.607990v1.49","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201604-0769OC"},{"key":"2024082603100942000_2024.08.20.607990v1.50","doi-asserted-by":"crossref","unstructured":"Walter, N. D. et al. Lung microenvironments harbor Mycobacterium tuberculosis phenotypes with distinct treatment responses. Antimicrob. Agents Chemother. 67, (2023).","DOI":"10.1128\/aac.00284-23"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.08.20.607990","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:54:45Z","timestamp":1768460085000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.08.20.607990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,21]]},"references-count":50,"URL":"https:\/\/doi.org\/10.1101\/2024.08.20.607990","relation":{},"subject":[],"published":{"date-parts":[[2024,8,21]]},"subtype":"preprint"}}