## 2 Main Components of the OxPhos Pathway in _M. tb_
### Terminal Oxidases
The upregulation of the cydAB operon has been reported for _M. tb_ under hypoxia and in the presence of NO, as well as during the chronic phase of infection in mice [72; 73; 74], and when the function of the Cyt-bcc-aa3 is compromised [75; 76; 77; 59; 61; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 75; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108;  
and drives a cycle of conformational changes in the catalytic F1 domain, resulting in successive ADP binding and entrapment, ADP phosphorylation to form ATP and ATP release [79]. Conventionally, the ATP synthase is also capable of ATPase activity when intracellular ATP levels are high and the PMF is low, hydrolysing ATP while pumping protons across the cytoplasm to re-energise the PMF [80]. In mycobacteria however, the ATP synthase has been characteristically observed to have suppressed ATP hydrolysis activity, which has been postulated to be an adaptation to conserving ATP under low oxygen tensions [39; 78; 81; 82]. In _M. tb_, the F1F0 ATP synthase is encoded by the atpBEFHAGDC operon and is essential for the viability of replicating and non-growing _M. tb_[31; 32; 33; 38], highlighting its critical role in ATP production and in maintaining a respiratory electron flow in all metabolic states [84]. Even though intracellular ATP levels in non-replicating _M. tb_ are significantly reduced compared to replicating bacilli, basal levels of ATP are still maintained in non-replicating states [19; 21]. The essentiality of the ATP synthase in these conditions is underlined by the fact that its pharmacological inhibition by BDQ, a specific ATP synthase inhibitor, kills hypoxic, non-replicating _M. tb_[83]. Interestingly, the mycobacterial ATP synthase is deprived of efficient ATP hydrolysis activity [82]. As a step towards uncovering the molecular basis of the extreme latency of ATP hydrolysis, a crystal structure of the _M. smeg_ catalytic F1 domain revealed similarities with the _Caldalkalibacillus thermarum_ F1-ATPase, which also hydrolyses ATP poorly [85]. This is likely due to an arrest in the catalytic rotary cycle of the F1 component, resulting in the inability to release products of ATP hydrolysis. The \(\varepsilon\)-subunit of the F1 module of _M. tb_, whose structure has been recently solved by nuclear magnetic resonance (NMR), has been implicated in the regulation of ATP hydrolysis. The removal of its C-terminal resulted in an increased ATP hydrolysis rate and decreased ATP synthesis [86]. Furthermore, [PERSON] et al., demonstrated that this site is amenable to chemical inhibition in _M. smeg_ by epigallocatechin gallate, the most abundant catechin in green tea [87]. Other subunits involved in the regulation of ATP hydrolysis include the \(\gamma\)- and \(\alpha\)- subunits of the F1 module [88; 89]. Altogether, these advances in the understanding of the F1F0 ATP synthase aid in identifying new, specific inhibitors that either block _de novo_ ATP synthesis and/or activate ATP hydrolysis, with the aim of depleting the residual pool of ATP in _M. tb_.