Roles of Alanine Dehydrogenase and Induction of Its Gene in Mycobacterium smegmatis under Respiration-Inhibitory Conditions.

Here we demonstrated that the inhibition of electron flux through the respiratory electron transport chain (ETC) by either the disruption of the gene for the major terminal oxidase ( cytochrome oxidase) or treatment with KCN resulted in the induction of encoding alanine dehydrogenase in A decrease in functionality of the ETC shifts the redox state of the NADH/NAD pool toward a more reduced state, which in turn leads to an increase in cellular levels of alanine by Ald catalyzing the conversion of pyruvate to alanine with the concomitant oxidation of NADH to NAD The induction of expression under respiration-inhibitory conditions in is mediated by the alanine-responsive AldR transcriptional regulator. The growth defect of by respiration inhibition was exacerbated by inactivation of the gene, suggesting that Ald is beneficial to in its adaptation and survival under respiration-inhibitory conditions by maintaining NADH/NAD homeostasis. The low susceptibility of to complex inhibitors appears to be, at least in part, attributable to the high expression level of the quinol oxidase in when the - branch of the ETC is inactivated. We demonstrated that the functionality of the respiratory electron transport chain is inversely related to the expression level of the gene encoding alanine dehydrogenase in Furthermore, the importance of Ald in NADH/NAD homeostasis during the adaptation of to severe respiration-inhibitory conditions was demonstrated in this study. On the basis of these results, we propose that combinatory regimens including both an Ald-specific inhibitor and respiration-inhibitory antitubercular drugs such as Q203 and bedaquiline are likely to enable a more efficient therapy for tuberculosis.