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We investigated whether the transcription factor network contributes to this adaptation. First, a responsive cohort of 709 genes diverged from the control, suggesting strong disturbance. While this was largely a direct effect of rifampicin, we show evidence that RNAP, \u03c3\n                      <jats:sup>70<\/jats:sup>\n                      , \u03c3\n                      <jats:sup>38<\/jats:sup>\n                      , Fnr, and (p)ppGpp were influential, suggesting early adaptations. We further show evidence that these responses can be promoter sequence dependent and are partially decoupled from changes in single-cell variability. Moreover, the responses of interacting genes were correlated, suggesting coordination. Later, the transcriptome partially realigned with the control, but 272 genes behaved consistently with long-term adaptation. Several exhibited correlated dynamics that can be explained by interactions, which form three independent, star-like modules of adaptive genes controlled by\n                      <jats:italic toggle=\"yes\">gcvB<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">cdaR<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">lldR<\/jats:italic>\n                      , respectively. Finally, we found that orthologous genes of the evolutionarily distant pathogen\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      have correlated response strengths to rifampicin, suggesting that our observations may be common across bacterial species. Overall, the results suggest that the initial effects of sublethal rifampicin concentrations on\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      \u2019s genome-wide transcriptional levels are dampened over time and then followed by a distinct state influenced by the gene network that may contribute to adaptation. These findings may assist in developing new strategies to disrupt bacterial adaptation to rifampicin.\n                    <\/jats:p>\n                    <jats:p>\n                      In natural environments, exposure to sublethal antibiotic (AB) stress is a common phenomenon that enhances the emergence of AB resistance. We dissected the genome-wide transcriptional program of\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      responsible for its initial response and subsequent adaptation to rifampicin. We show that the transcription factor network plays a major role in this program and provide evidence that the transcriptome response patterns are conserved in the evolutionarily distant pathogen\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      . Our findings may assist in developing new strategies to disrupt bacterial adaptation to rifampicin.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.00808-26","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:39:21Z","timestamp":1788367161000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Distinct transcription factor network dynamics underlie early and long-term adaptation to rifampicin in\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1128","volume":"11","author":[{"given":"M. M.","family":"Azevedo","sequence":"first","affiliation":[{"name":"Laboratory of Biosystem Dynamics, Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1431-9816","authenticated-orcid":true,"given":"A. M.","family":"Arsh","sequence":"additional","affiliation":[{"name":"Laboratory of Biosystem Dynamics, Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Jagadeesan","sequence":"additional","affiliation":[{"name":"Laboratory of Biosystem Dynamics, Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Ravaria","sequence":"additional","affiliation":[{"name":"Laboratory of Biosystem Dynamics, Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-5211","authenticated-orcid":true,"given":"Andre S.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Laboratory of Biosystem Dynamics, Faculty of Medicine and 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