FIG. 1.

Redox machinery of Mtb. During infection, Mtb encounters redox active compounds that have the capacity to alter or skew intracellular redox balance. Mtb has evolved several mechanisms to maintain redox homeostasis. Mtb utilizes host lipids as a source of carbon in vivo, which are metabolized via the (-oxidation pathway. This leads to the generation of high concentrations of NAD(P)H during the conversion of fatty acids to acetate and propionate. The accumulation of high levels of NAD(P)H causes reductive stress in Mtb (18, 40). Furthermore, host-generated free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) are also capable of disturbing Mtb redox balance. However, Mtb counterbalances the stress generated by these radicals primarily via the abundant intracellular redox buffer, mycothiol (MSH). In addition, protein thiols and mycobacterial thioredoxins (Trx) are also involved in detoxifying the adverse effect of free radicals. Another yet uncharacterized redox active molecule, ergothioneine (Erg), is also expected to play a role in detoxification of free radicals and maintaining redox balance. Endogenous byproducts of mycobacterial respiration such as H₂O₂ and O₂^•− may react with mycobacterial lipids to generate lipid peroxides. In the presence of iron or copper, these ROS can generate the highly redox active OH^•. ROS or RNS such as peroxide, peroxynitrous acid (ONOOH), and peroxynitrite (ONOO^-), and compounds such as vitamin C (in the presence of metal ions) may also lead to the production of intramycobacterial OH^• that can cause the oxidation of intracellular substrates. Host-generated gases also play a role in inducing mycobacterial redox changes. Mtb has well-defined sensor systems such as the DosS/T/R and WhiB3 signaling pathways, which specifically sense NO, CO, and changes in pO₂. CO, NO, and O₂ interact with the Dos signaling pathway, leading to the induction of the 47-member Dos regulon. It also leads to the production of the storage lipid TAG, which requires large quantities of NAD(P)H for synthesis. Similarly, WhiB3 also senses and responds to alterations in cytoplasmic NO and O₂. Mrx; mycoredoxin, Mtr; mycothiol disulfide reductase.