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The genome of\n                      <jats:italic toggle=\"yes\">Mycobacterium smegmatis<\/jats:italic>\n                      encodes two cAMP receptor proteins (Crp), MSMEG_6189 (Crp1) and MSMEG_0539 (Crp2). The deletion of\n                      <jats:italic toggle=\"yes\">crp1<\/jats:italic>\n                      markedly increased susceptibility to INH, whereas the deletion of\n                      <jats:italic toggle=\"yes\">crp2<\/jats:italic>\n                      had no effect. In contrast, susceptibility to rifampicin was unchanged in the \u0394\n                      <jats:italic toggle=\"yes\">crp1<\/jats:italic>\n                      mutant. Gene expression analysis revealed strong upregulation of\n                      <jats:italic toggle=\"yes\">katG1<\/jats:italic>\n                      , which encodes the INH-activating catalase-peroxidase, and an almost complete abolishment of\n                      <jats:italic toggle=\"yes\">ahpC<\/jats:italic>\n                      expression, which encodes alkyl hydroperoxide reductase and contributes to INH resistance, in the \u0394\n                      <jats:italic toggle=\"yes\">crp1<\/jats:italic>\n                      mutant. The mutant also exhibited elevated intracellular reactive oxygen species (ROS) levels and reduced respiration. These elevated ROS levels likely resulted from alterations in the respiratory electron transport chain, including reduced levels of the cytochrome\n                      <jats:italic toggle=\"yes\">bcc<\/jats:italic>\n                      <jats:sub>1<\/jats:sub>\n                      complex, increased expression of the\n                      <jats:italic toggle=\"yes\">nuo<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">sdh1<\/jats:italic>\n                      operons (encoding type I NADH dehydrogenase and succinate dehydrogenase, respectively), and the loss of\n                      <jats:italic toggle=\"yes\">bd<\/jats:italic>\n                      quinol oxidase induction under conditions of diminished\n                      <jats:italic toggle=\"yes\">bcc<\/jats:italic>\n                      <jats:sub>1<\/jats:sub>\n                      complex levels. ROS accumulation, in turn, appears to inactivate the FurA repressor, leading to the induction of\n                      <jats:italic toggle=\"yes\">katG1<\/jats:italic>\n                      expression. Collectively, these findings suggest that the loss of Crp1 increases INH susceptibility through multiple mechanisms that promote INH activation, including ROS-mediated induction of\n                      <jats:italic toggle=\"yes\">katG1<\/jats:italic>\n                      and increased intracellular ROS levels. Furthermore, the absence of\n                      <jats:italic toggle=\"yes\">ahpC<\/jats:italic>\n                      expression in the \u0394\n                      <jats:italic toggle=\"yes\">crp1<\/jats:italic>\n                      mutant further contributes to its increased INH susceptibility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      This study revealed that the cAMP receptor protein, Crp1, plays a role in controlling key genes involved in both INH activation (\n                      <jats:italic toggle=\"yes\">katG1<\/jats:italic>\n                      ) and resistance (\n                      <jats:italic toggle=\"yes\">ahpC<\/jats:italic>\n                      ) in\n                      <jats:italic toggle=\"yes\">Mycobacterium smegmatis<\/jats:italic>\n                      . Inactivation of Crp1 was shown to cause an increase in cellular ROS levels, which likely results from a bottleneck of electron flow at the cytochrome\n                      <jats:italic toggle=\"yes\">bcc<\/jats:italic>\n                      <jats:sub>1<\/jats:sub>\n                      complex in the electron transport chain and the abolishment of\n                      <jats:italic toggle=\"yes\">bd<\/jats:italic>\n                      quinol oxidase induction under conditions of reduced\n                      <jats:italic toggle=\"yes\">bcc1<\/jats:italic>\n                      complex levels. The resulting increase in ROS, combined with the simultaneous loss of\n                      <jats:italic toggle=\"yes\">ahpC<\/jats:italic>\n                      expression, renders the bacterium significantly more vulnerable to INH. These findings provide deeper insights into the interplay among oxidative phosphorylation, ROS generation, and INH susceptibility.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00429-25","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T13:01:16Z","timestamp":1763989276000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Inactivation of cAMP receptor protein (MSMEG_6189) increases isoniazid susceptibility in\n                    <i>Mycobacterium smegmatis<\/i>\n                    via altered oxidative phosphorylation, elevated ROS production, and loss of\n                    <i>ahpC<\/i>\n                    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