Inactivation of cAMP receptor protein (MSMEG_6189) increases isoniazid susceptibility in <i>Mycobacterium smegmatis</i> via altered oxidative phosphorylation, elevated ROS production, and loss of <i>ahpC</i> expression

This study revealed that the cAMP receptor protein, Crp1, plays a role in controlling key genes involved in both INH activation (<i>katG1</i>) and resistance (<i>ahpC</i>) in <i>Mycobacterium smegmatis</i>. 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 <i>bcc</i>₁ complex in the electron transport chain and the abolishment of <i>bd</i> quinol oxidase induction under conditions of reduced <i>bcc1</i> complex levels. The resulting increase in ROS, combined with the simultaneous loss of <i>ahpC</i> 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.